Pavlov Et Al-2019-Cochrane Database of Systematic Reviews

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Glucocorticosteroids for people with alcoholic hepatitis (Review)
Pavlov CS, Varganova DL, Casazza G, Tsochatzis E, Nikolova D, Gluud C
Pavlov CS, Varganova DL, Casazza G, Tsochatzis E, Nikolova D, Gluud C.

Glucocorticosteroids for people with alcoholic hepatitis.
Cochrane Database of Systematic Reviews 2019, Issue 4. Art. No.: CD001511.
DOI: 10.1002/14651858.CD001511.pub4.
www.cochranelibrary.com

Copyright © 2019 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
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TABLE OF CONTENTS
HEADER......................................................................................................................................................................................................... 1
ABSTRACT..................................................................................................................................................................................................... 1
PLAIN LANGUAGE SUMMARY....................................................................................................................................................................... 2
SUMMARY OF FINDINGS.............................................................................................................................................................................. 4
BACKGROUND.............................................................................................................................................................................................. 7
OBJECTIVES.................................................................................................................................................................................................. 8
METHODS..................................................................................................................................................................................................... 8
RESULTS........................................................................................................................................................................................................ 12
Figure 1.................................................................................................................................................................................................. 13
Figure 2.................................................................................................................................................................................................. 16
Figure 3.................................................................................................................................................................................................. 17
Figure 4.................................................................................................................................................................................................. 18
Figure 5.................................................................................................................................................................................................. 19
Figure 6.................................................................................................................................................................................................. 20
Figure 7.................................................................................................................................................................................................. 21
Figure 8.................................................................................................................................................................................................. 23
Figure 9.................................................................................................................................................................................................. 24
Figure 10................................................................................................................................................................................................ 25
Figure 11................................................................................................................................................................................................ 26
DISCUSSION.................................................................................................................................................................................................. 27
AUTHORS' CONCLUSIONS........................................................................................................................................................................... 28
ACKNOWLEDGEMENTS................................................................................................................................................................................ 29
REFERENCES................................................................................................................................................................................................ 30
CHARACTERISTICS OF STUDIES.................................................................................................................................................................. 38
DATA AND ANALYSES.................................................................................................................................................................................... 69
Analysis 1.1. Comparison 1 Glucocorticosteroids versus placebo/no intervention, Outcome 1 All-cause mortality....................... 70
Analysis 1.2. Comparison 1 Glucocorticosteroids versus placebo/no intervention, Outcome 2 Health-related quality of life........ 71
Analysis 1.3. Comparison 1 Glucocorticosteroids versus placebo/no intervention, Outcome 3 Serious adverse events during 71
treatment...............................................................................................................................................................................................
Analysis 1.4. Comparison 1 Glucocorticosteroids versus placebo/no intervention, Outcome 4 Liver-related mortality: up to 3 72
months' follow-up after randomisation..............................................................................................................................................
Analysis 1.5. Comparison 1 Glucocorticosteroids versus placebo/no intervention, Outcome 5 Participants with any complication 73
up to 3 months' follow-up....................................................................................................................................................................
Analysis 1.6. Comparison 1 Glucocorticosteroids versus placebo/no intervention, Outcome 6 Participants with non-serious 73
adverse events up to 3 months' follow-up after randomisation.......................................................................................................
Analysis 2.1. Comparison 2 Subgroup analysis: all-cause mortality up to 3 months' follow-up after randomisation, Outcome 1 75
Bias risk..................................................................................................................................................................................................
Trials without for-profit funding compared to trials at risk of for-profit funding.............................................................................
Severity of alcoholic hepatitis..............................................................................................................................................................
Glucocorticosteroid (prednisolone) dose............................................................................................................................................
Alcoholic hepatitis without or with cirrhosis......................................................................................................................................
Alcoholic hepatitis without or with hepatorenal syndrome..............................................................................................................
Alcoholic hepatitis without or with ascites.........................................................................................................................................
Analysis 3.1. Comparison 3 Sensitivity analysis: all-cause mortality, Outcome 1 Best-worst scenario all-cause mortality up to 3 80
months' follow-up after randomisation..............................................................................................................................................
Analysis 3.2. Comparison 3 Sensitivity analysis: all-cause mortality, Outcome 2 Worst-best scenario analysis: all-cause mortality 81
up to 3 months' follow-up after randomisation.................................................................................................................................
Glucocorticosteroids for people with alcoholic hepatitis (Review) i

Informed decisions.
Analysis 4.1. Comparison 4 Sensitivity analysis: serious adverse events, Outcome 1 Best-worse scenario of serious adverse 82
events during treatment.......................................................................................................................................................................
Analysis 4.2. Comparison 4 Sensitivity analysis: serious adverse events, Outcome 2 Worst-best scenario of serious adverse 82
events during treatment.......................................................................................................................................................................
ADDITIONAL TABLES.................................................................................................................................................................................... 84
APPENDICES................................................................................................................................................................................................. 85
WHAT'S NEW................................................................................................................................................................................................. 89
CONTRIBUTIONS OF AUTHORS................................................................................................................................................................... 89
DECLARATIONS OF INTEREST..................................................................................................................................................................... 89
SOURCES OF SUPPORT............................................................................................................................................................................... 89
DIFFERENCES BETWEEN PROTOCOL AND REVIEW.................................................................................................................................... 89
NOTES........................................................................................................................................................................................................... 90
INDEX TERMS............................................................................................................................................................................................... 90
Glucocorticosteroids for people with alcoholic hepatitis (Review) ii

Informed decisions.
[Intervention Review]
Glucocorticosteroids for people with alcoholic hepatitis
Chavdar S Pavlov1,2,3, Daria L Varganova1,3,4, Giovanni Casazza5,6, Emmanuel Tsochatzis7, Dimitrinka Nikolova1, Christian Gluud1
1Cochrane Hepato-Biliary Group, Copenhagen Trial Unit, Centre for Clinical Intervention Research, Department 7812, Rigshospitalet,
Copenhagen University Hospital, Copenhagen, Denmark. 2Kazan Federal University, Kazan, Russian Federation. 3'Sechenov' First
Moscow State Medical University, Center for Evidence-Based Medicine, Moscow, Russian Federation. 4Department of Gastroenterology,
Ulyanovsk Regional Clinical Hospital, Ulyanovsk, Russian Federation. 5Dipartimento di Scienze Biomediche e Cliniche "L. Sacco",
Università degli Studi di Milano, Milan, Italy. 6The Cochrane Hepato-Biliary Group, Copenhagen Trial Unit, Centre for Clinical Intervention
Research, Department 7812, Rigshospitalet, Copenhagen University Hospital, Copenhagen, Denmark. 7Sheila Sherlock Liver Centre,
Royal Free Hospital and the UCL Institute of Liver and Digestive Health, London, UK
Contact address: Chavdar S Pavlov, Cochrane Hepato-Biliary Group, Copenhagen Trial Unit, Centre for Clinical Intervention Research,
Department 7812, Rigshospitalet, Copenhagen University Hospital, Blegdamsvej 9, Copenhagen, DK-2100, Denmark. chpavlov@mail.ru.
Editorial group: Cochrane Hepato-Biliary Group.

Publication status and date: New search for studies and content updated (no change to conclusions), published in Issue 4, 2019.
Citation: Pavlov CS, Varganova DL, Casazza G, Tsochatzis E, Nikolova D, Gluud C. Glucocorticosteroids for people with alcoholic
hepatitis. Cochrane Database of Systematic Reviews 2019, Issue 4. Art. No.: CD001511. DOI: 10.1002/14651858.CD001511.pub4.
ABSTRACT
Background
Alcoholic hepatitis is a form of alcoholic liver disease characterised by steatosis, necroinflammation, fibrosis, and complications to the
liver. Typically, alcoholic hepatitis presents in people between 40 and 50 years of age. Alcoholic hepatitis can be resolved if people abstain
from drinking, but the risk of death will depend on the severity of the liver damage and abstinence from alcohol. Glucocorticosteroids have
been studied extensively in randomised clinical trials to assess their benefits and harms. However, the results have been contradictory.
Objectives
To assess the benefits and harms of glucocorticosteroids in people with alcoholic hepatitis.
Search methods
We identified trials through electronic searches in Cochrane Hepato-Biliary's (CHB) Controlled Trials Register, CENTRAL, MEDLINE, Embase,
LILACS, and Science Citation Index Expanded. We looked for ongoing or unpublished trials in clinical trials registers and pharmaceutical
company sources. We also scanned reference lists of the studies retrieved. The last search was 18 January 2019.
Selection criteria
Randomised clinical trials assessing glucocorticosteroids versus placebo or no intervention in people with alcoholic hepatitis, irrespective
of year, language of publication, or format. We considered trials with adults diagnosed with alcoholic hepatitis, which could have been
established through clinical or biochemical diagnostic criteria or both. We defined alcoholic hepatitis as mild (Maddrey's score less than
32) and severe (Maddrey's score 32 or more). We allowed cointerventions in the trial groups, provided they were similar.
Data collection and analysis

We followed Cochrane methodology, performing the meta-analyses using Review Manager 5. We presented the results of dichotomous
outcomes as risk ratios (RR) and of continuous outcomes as mean difference (MD), with 95% confidence intervals (CI). We used both the
fixed-effect and the random-effects models for meta-analyses. Whenever there were significant discrepancies in the results, we reported
the more conservative point estimate of the two. We considered a P value of 0.01 or less, two-tailed, as statistically significant if the required
information size was reached for our three primary outcomes (all-cause mortality, health-related quality of life, and serious adverse events
during treatment) and our post hoc decision to include analyses of mortality at more time points. We presented heterogeneity using the
Glucocorticosteroids for people with alcoholic hepatitis (Review) 1
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I2 statistic. If trialists used intention-to-treat analysis to deal with missing data, we used these data in our primary analysis; otherwise, we
used the available data. We assessed the bias risk of the trials using bias risk domains and the certainty of the evidence using GRADE.
Main results
Sixteen trials fulfilled our inclusion criteria. All trials but one were at overall high risk of bias. Fifteen trials (one of which was an abstract)
provided data for analysis (927 participants received glucocorticosteroids and 934 participants received placebo or no intervention).
Glucocorticosteroids were administered orally or parenterally for a median 28 days (range 3 days to 12 weeks). The participants were
between 25 and 70 years old, had different stages of alcoholic liver disease, and 65% were men. Follow-up, when reported, was up to
the moment of discharge from the hospital, until they died (median of 63 days), or for at least one year. There was no evidence of effect
of glucocorticosteroids on all-cause mortality up to three months following randomisation (random-effects RR 0.90, 95% CI 0.70 to 1.15;
participants = 1861; trials = 15; very low-certainty evidence) or on health-related quality of life up to three months, measured with the
European Quality of Life – 5 Dimensions – 3 Levels scale (MD –0.04 points, 95% CI –0.11 to 0.03; participants = 377; trial = 1; low-certainty
evidence). There was no evidence of effect on the occurrence of serious adverse events during treatment (random-effects RR 1.05, 95% CI
0.85 to 1.29; participants = 1861; trials = 15; very low-certainty evidence), liver-related mortality up to three months following randomisation
(random-effects RR 0.89, 95% CI 0.69 to 1.14; participants = 1861; trials = 15; very low-certainty evidence), number of participants with
any complications up to three months following randomisation (random-effects RR 1.04, 95% CI 0.86 to 1.27; participants = 1861; very
low-certainty evidence), and number of participants of non-serious adverse events up to three months' follow-up after end of treatment
(random-effects RR 1.99, 95% CI 0.72 to 5.48; participants = 160; trials = 4; very low-certainty evidence). Based on the information that we
collected from the published trial reports, only one of the trials seems not to be industry-funded, and the remaining 15 trials did not report
clearly whether they were partly or completely funded by the industry.
Authors' conclusions
We are very uncertain about the effect estimate of no difference between glucocorticosteroids and placebo or no intervention on all-cause
mortality and serious adverse events during treatment because the certainty of evidence was very low, and low for health-related quality
of life. Due to inadequate reporting, we cannot exclude increases in adverse events. As the CIs were wide, we cannot rule out significant
benefits or harms of glucocorticosteroids. Therefore, we need placebo-controlled randomised clinical trials, designed according to the
SPIRIT guidelines and reported according to the CONSORT guidelines. Future trials ought to report depersonalised individual participant
data, so that proper individual participant data meta-analyses of the effects of glucocorticosteroids in subgroups can be conducted.
PLAIN LANGUAGE SUMMARY
Review question
To assess the benefits and harms of glucocorticosteroids administered at any route, dose, and duration versus placebo or no intervention
in people with alcoholic hepatitis in terms of death, health-related quality of life, and complications.
Background
Excessive alcoholic consumption may damage the liver, causing alcoholic hepatitis. The first stage of liver damage in alcoholic hepatitis is
usually reversible if people abstain from drinking, but the risk of the disease developing further and getting more complications increases
with resumed drinking. A heavy drinker is considered a person who consumes more than 30 g (for men) or more than 20 g (for women)
of alcohol per day. Only 10 to 35 people out of 100 heavy drinkers with evidence of excessive fat in the liver would most probably
develop alcoholic hepatitis. With time, alcoholic hepatitis will cause liver fibrosis (scarring of the liver) or liver cirrhosis with complications
(bleeding, infections, liver cancer, etc.).
Glucocorticosteroids are considered to have anti-inflammatory effects (relieving pain, swelling (oedema), fever). They are administered to
people with alcoholic hepatitis in order to repair their liver injury. However, the benefits and harms of glucocorticosteroids are not well
studied in randomised clinical trials (studies where people are randomly put into one of two or more treatment groups), and therefore, it
is uncertain if they should be used in clinical practice for people with alcoholic liver disease.
Search date
The date of the last search was 18 January 2019.
Study characteristics
Sixteen randomised clinical trials compared glucocorticosteroids with placebo or no intervention in people with alcoholic hepatitis. Fifteen
trials provided data for analysis (927 participants received glucocorticosteroids and 934 participants received placebo or no intervention).
Glucocorticosteroids were administered orally or as an injection for a median of 28 days (range 3 days to 12 weeks). The trial participants
were between 25 and 70 years old, 65% were men, and had different stages of alcoholic liver disease. Trial participants were followed up to
the moment of discharge from the hospital, or until they died (a median of 63 days), or for at least one year. Not all trials reported the follow-

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up of participants. The trials were conducted in France, India, the UK, and the USA. Two trials administered pentoxifylline (a medicine used
for diseases of the blood vessels) to both glucocorticosteroids and placebo intervention groups.
Funding
Based on the information that we collected from the published trial reports, only one of the trials seems not to be industry-funded, and
the remaining 15 trials did not report clearly whether they were partly or completely funded by the industry.
Reliability of the evidence
The overall reliability of the evidence was low for health-related quality of life and very low for death due to any cause up to three months
following entry in the trial; serious side effects during treatment; liver-related death up to three months following entry in the trial; number
of participants with any complications up to three months following entry in the trial, and number of participants non-serious side effects
up to three months' follow-up after the end of treatment. All trials but one were at overall high risk of bias, which means that there is
possibility of drawing wrong conclusions, exaggerating benefits, or underestimating harms of glucocorticosteroids because of the way the
trials were conducted and analysed.
Key results
We could not determine whether glucocorticosteroids had a positive or negative effect on people with alcoholic liver disease. Despite
available data on outcomes which included mortality, health-related quality of life, and serious complications, we were unable to draw firm
conclusions mainly because available data were still insufficient to produce robust results, trials were small, and the included participants
differed in severity of disease. Therefore, we have very little confidence in our conclusions.

SUMMARY OF FINDINGS
Summary of findings for the main comparison. Glucocorticosteroids for people with alcoholic hepatitis
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Patient or population: participants with alcoholic hepatitis at high risk of mortality and morbidity
Settings: hospitals and clinics
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Intervention: glucocorticosteroids
Comparison: placebo or no intervention
Outcomes Illustrative comparative risks* (95% Relative effect No of partici- Certainty of Comments
CI) (95% CI) pants the evidence
(studies) (GRADE)
Assumed risk Corresponding
risk
Placebo or no Glucocorticos-
intervention teroids
All-cause mortality: up to 3 months' 299 per 1000 278 per 1000 RR 0.90 1861 ⊕⊝⊝⊝ We downgraded for inconsis-
follow-up after randomisation Very lowa tency because of selection
(210 to 344) (0.70 to 1.15) (15 RCTs) bias in the trials: trials either
included or excluded people
with gastrointestinal haemor-
rhage, active peptic ulcer dis-
ease, pancreatitis, renal fail-
ure, bacterial infections.
The OIS was 7870 partici-

pants.

Health-related quality of life: up to 3 The mean value The mean value MD –0.04 (–0.11 377 ⊕⊕⊝⊝ —
months was 0.592 was 0.553 to 0.03)
(1 RCT) Lowc
(measured with European Quali- (0.502 to 0.604)
ty of Life – 5 Dimensions – 3 Levels
(EQ-5D-3L)b scale)
Serious adverse events during treat- 362 per 1000 381 per 1000 RR 1.05 1861 ⊕⊝⊝⊝ The OIS was 4197 partici-
ment Very lowd pants.
(398 to 467) (0.85 to (15 RCTs)
4
1.29)
Liver-related mortality: up to 3 299 per 1000 267 per 1000 RR 0.89 1861 ⊕⊝⊝⊝ The OIS was 7987 partici-
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months' follow-up after randomisa- Very lowe pants.
tion (207 to 341) (0.69 to 1.14) (15 RCTs)
Participants with any complication: 444 per 1000 462 per 1000 RR 1.04 1861 ⊕⊝⊝⊝ The OIS was 5980 partici-
up to 3 months following randomi- Very lowf pants.
sation (382 to 564) (0.86 to 1.27) (15 RCTs)
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Participants with non-serious ad- 52 per 1000 104 per 1000 RR 1.99 160 ⊕⊝⊝⊝ The OIS was 2698 partici-
verse events: up to 3 months' fol- Very lowg pants.
low-up after randomisation (38 to 285) (0.72 to 5.48) (4 RCTs)
*The basis for the assumed risk (e.g. the median control group risk across studies) is provided in footnotes. The corresponding risk (and its 95% confidence interval) is
based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI).
CI: confidence interval; MD: mean difference; OIS: optimal information size; RCT: randomised controlled trial; RR: risk ratio.
GRADE Working Group: certainty of evidence grades
High certainty: we are very confident that the true effect lies close to that of the estimate of the effect.
Moderate certainty: we are moderately confident in the effect estimate: the true effect is likely to be close to the estimate of the effect, but there is a possibility that it is
substantially different.
Low certainty: our confidence in the effect estimate is limited: the true effect may be substantially different from the estimate of the effect.
Very low certainty: we have very little confidence in the effect estimate: the true effect is likely to be substantially different from the estimate of effect.
aDowngraded three levels: one level due to within-study risk of bias (high overall risk of bias in all the trials but one (Thursz 2015); one level due to inconsistency of the data (there
is wide variation in the effect estimates across studies; there is little overlap of confidence intervals associated with the effect estimates; presence of moderate heterogeneity: I2
= 45%; heterogeneity could be explained with selection bias); one level due to imprecision (the OIS was not reached).
bEQ-5D-5L: a self-report, multiple-choice questionnaire that provides a simple descriptive profile and a single index value for health status. The EQ-5D-5L essentially consists
of two pages: the EQ-5D descriptive system (on page 2) and the EQ visual analogue scale (EQ VAS) (on page 3). The descriptive system comprises the following five dimensions:
mobility, self-care, usual activities, pain/discomfort, and anxiety/depression. Each dimension has five levels: no problems; slight problems; moderate problems; severe problems;
and extreme problems. The EQ VAS records the respondent's self-rated health on a vertical, visual analogue scale. A summary index with a maximum score of 1 can be derived

from these five dimensions by conversion with a table of scores. The maximum score of 1 indicates the best health state, by contrast with the scores of individual questions,
where higher scores indicate more severe or frequent problems. Utility values for perfect health and death are 1 and 0, respectively. In addition, there is a visual analogue scale
to indicate the general health status with 100 indicating the best health status.
cDowngraded two levels: one level due to within-study risk of bias (high overall risk of bias in the trial); one level due to imprecision of effect estimates (fewer than 400 participants).
dDowngraded three levels: one level due to within-study risk of bias (high overall risk of bias in all the trials but one); one level due to inconsistency of the data (there was wide
variation in the effect estimates across studies; there was little overlap of confidence intervals associated with the effect estimates; presence of moderate heterogeneity: I2 = 36%;
heterogeneity could be explained with selection bias); one level due to imprecision (the OIS was not reached).
eDowngraded three levels: one level due to within-study risk of bias (high overall risk of bias in all the trials but one); one level due to inconsistency of the data (there is wide
variation in the effect estimates across studies; there is little overlap of confidence intervals associated with the effect estimates; presence of moderate heterogeneity: I2 = 46%;
5
fDowngraded three levels: one level due to within-study risk of bias (high overall risk of bias in all the trials but one); one level due to inconsistency of the data (there was wide
variation in the effect estimates across studies; there was little overlap of confidence intervals associated with the effect estimates; presence of moderate heterogeneity: I2 = 41%;
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gDowngraded four levels: one level due to within-study risk of bias (high overall risk of bias in all the trials but one); one level due to inconsistency of the data (there is little
overlap of confidence intervals associated with the effect estimates); one level due to publication bias (only four trials with a small number of participants reported on non-
serious adverse events); one level due to imprecision (the OIS was not reached).
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6
Informed decisions.
BACKGROUND failure to respond to treatment and predicts a six-month mortality

of about 75% (Lefkowitch 2005).
Description of the condition
Description of the intervention
The term 'alcoholic hepatitis' was used for the first time in a
paper by Beckett and colleagues in 1961 (Beckett 1961), but clinical Glucocorticosteroids are used as anti-inflammatory drugs.
jaundice after excessive ethanol consumption was reported in the Glucocorticosteroid agents mimic the endogenously produced
literature long before that, in 1912 (French 1912; Gerber 1973). Most glucocorticoid (cortisol) (Rhen 2005). Glucocorticosteroids,
probably, these reports represented people with alcoholic hepatitis primarily regulated by corticotropin, are considered to have anti-
(Mendenhall 1984; Jensen 1994). inflammatory effects as well as metabolic and immunogenic effects
(Rhen 2005). It is agreed that the anti-inflammatory effects of
Alcoholic hepatitis is a serious form of alcoholic liver disease (injury glucocorticosteroids are mediated primarily through repression of
of the liver due to excessive alcohol consumption) (WHO 2010). gene transcription (Schäcke 2002).
The first stage of liver damage in alcoholic hepatitis is usually How the intervention might work
reversible if people abstain from drinking, but the risk of
progression to fibrosis and cirrhosis increases with resumed Glucocorticosteroids administered to people with alcoholic
drinking (Ellis 2012). The accumulation of fat in the hepatocytes hepatitis repair the liver injury by decreasing the liver
causes disruption of the mitochondrial beta-oxidation of fatty polymorphonuclear neutrophil (PMN) (effector cells) infiltrates and
acids, accumulation of lipotoxic metabolites, and release of the level of proinflammatory mediators such as tumour necrosis
reactive oxygen species (Lieber 1999; Wu 1999; Petrasek 2013). factor-alpha (TNF-alpha), intercellular adhesion molecule 1, and
Lipotoxic metabolites and reactive oxygen species lead to cell interleukin (IL)-6 and IL-8 in the liver tissue (Taïeb 2000; Spahr 2001).
death and liver inflammation (Wu 1999; Petrasek 2013; WHO 2013). The benefits of corticosteroids ensue from short-term vascular
Alcoholic hepatitis is a histological form of alcoholic liver disease, changes (Schäcke 2002). However, adverse events have still been
characterised by steatosis (the earliest stage of alcoholic liver poorly reported (Christensen 1995; Rambaldi 2008).
damage) and necroinflammation (EASL 2018). Alcoholic hepatitis
can be resolved if people abstain from drinking, but the risk of Why it is important to do this review
death will depend on the severity of the liver damage and drinking Several randomised clinical trials have studied the benefits and
patterns. In 20% to 40% of persistent heavy drinkers (defined as harms of corticosteroids for people with alcoholic hepatitis to
alcohol consumption per day of more than 30 g in men (EASL 2018) determine the best route of administration, dose, and duration.
and more than 20 g in women (EASL 2018), alcoholic hepatitis and However, results have been contradictory. Some systematic
other complications may develop (WHO 2013). reviews (Christensen 1995; Rambaldi 2008), and meta-analyses
of randomised clinical trials (Reynolds 1989; Imperiale 1990;
Severe alcoholic hepatitis may be characterised by clinically Daures 1991; Christensen 1999; Mathurin 2011; Louvet 2018),
clear signs of jaundice, coagulopathy, liver decompensation have been published. The review authors explained their various
with ascites, portal hypertension, variceal bleeding, hepatorenal conclusions regarding patient-orientated outcomes as being
syndrome, hepatic encephalopathy, systemic inflammatory due to differences in glucocorticosteroid regimens, trial quality,
response syndrome, or sepsis (Becker 1996; EASL 2018). Typically, participants' characteristics, and clinical spectrum of the disease.
alcoholic hepatitis presents in people aged between 40 and 50 Reynolds 1989 concluded that corticosteroid treatment could
years. Among the risk factors of developing severe alcoholic help only the most severely ill people with severe alcoholic
hepatitis are being female, Hispanic ethnicity, various types of hepatitis characterised by high levels of serum bilirubin, prolonged
alcohol, binge drinking, poor nutrition, obesity, etc. (WHO 2010). prothrombin times, and development of hepatic encephalopathy.
Several composite prognostic scores exist to distinguish people Imperiale 1990 concluded that glucocorticosteroids reduced short-
with poor prognosis from those who can become abstinent, term mortality in people with severe alcoholic hepatitis, provided
instituting supportive care, until recovery is achieved. Some that they also had hepatic encephalopathy but did not have
of these scores, designed to predict mortality, are Maddrey's severe gastrointestinal bleeding. Daures 1991 concluded that
discriminant function (Maddrey 1978), the model of end-stage further randomised clinical trials were needed to confirm the
liver disease (MELD) score (Dunn 2005); the Glasgow alcoholic benefits and harms of glucocorticosteroids, especially in people
hepatitis score (Forrest 2005); and the age, bilirubin, international with severe alcoholic hepatitis. Christensen 1995, Christensen 1999,
normalised ratio, creatinine (ABIC) score (Dominguez 2008). and Rambaldi 2006 could not find sufficient proof supporting
The Maddrey Discriminant Function is the most often used the routine use of glucocorticosteroids in people with alcoholic
score in severe alcoholic hepatitis to identify people in potential hepatitis, including those with hepatic encephalopathy. Rambaldi
need of glucocorticosteroids (also known as glucocorticoids, 2008 concluded that glucocorticosteroids did not improve overall
corticosteroids, or steroids). The one-month survival of people with survival in people with alcoholic hepatitis. Based on the Trial
alcoholic hepatitis and with Maddrey's score higher than 32 varied Sequential Analysis of the subgroup of people with Maddrey's
between 50% and 65% (Carithers 1989; Phillips 2006). The Lille score of at least 32 or spontaneous hepatic encephalopathy, the
Model (www.lillemodel.com) is the only validated model so far required information size of 2420 people for the outcome mortality
to assess glucocorticosteroid response and is highly predictive of was far from reached, with only 249 participants randomised in
death at six months (P < 0.001) in people with severe alcoholic the six trials (Rambaldi 2008). Using the Lille Model, Mathurin
hepatitis (Louvet 2007). A Lille Model score greater than 0.45, 2011 concluded that glucocorticosteroids significantly improved
calculated after seven days of treatment with prednisolone, means 28-day survival in people with severe alcoholic hepatitis. Mathurin
2011 based the meta-analysis on individual patient data from five

Informed decisions.
selected randomised clinical trials and was accordingly at risk of Types of interventions
preferential selection. In 2018, Louvet and colleagues published
Glucocorticosteroids administered by any route, dose, and duration
four meta-analyses in one publication in which they assessed the
versus placebo or no intervention.
effects of corticosteroids versus placebo or control, corticosteroids
versus pentoxifylline, corticosteroids plus pentoxifylline versus We allowed cointerventions in the trial groups, provided they were
corticosteroids plus placebo or control, and pentoxifylline versus the same.
placebo in four meta-analyses (Louvet 2018). The conclusions
Louvet and colleagues made was that corticosteroids reduced Types of outcome measures
the risk of death within 28 days of treatment, but not in the
next six months. However, Louvet 2018 did not contain new Primary outcomes
references to randomised clinical trials of interest to our review. • All-cause mortality: up to three months' follow-up after
The present review is an update of our previously published randomisation (the primary time point for drawing our main
Cochrane systematic review, assessing the benefits and harms of conclusion); at the end of treatment (post hoc analysis); and one
glucocorticosteroids in people with severe alcoholic hepatitis with year following randomisation (post hoc analysis).
or without complications. • Health-related quality of life as defined by the trial authors.
OBJECTIVES • Serious adverse events during treatment. We used the
International Conference on Harmonisation (ICH) Guidelines for
To assess the benefits and harms of glucocorticosteroids in people Good Clinical Practice's definition of a serious adverse event
with alcoholic hepatitis. (ICH-GCP 1997), that is, any untoward medical occurrence that
resulted in death, was life threatening, required hospitalisation
METHODS or prolongation of existing hospitalisation, resulted in persistent
or significant disability or incapacity, or was a congenital
Criteria for considering studies for this review anomaly or birth defect. We considered all other adverse events
as non-serious (see Secondary outcomes).
Types of studies
We included randomised clinical trials in which Secondary outcomes
glucocorticosteroids were assessed in people with alcoholic • Liver-related mortality up to three months' follow-up after
hepatitis, irrespective of year or language of publication or format. randomisation.
We found no reports of harm in the quasi-randomised or • Participants with any complication up to three months' follow-
observational studies retrieved with our searches for randomised up after randomisation (i.e. ascites, hepatorenal syndrome,
clinical trials (Excluded studies). spontaneous bacterial peritonitis, gastrointestinal bleeding,
hepatic encephalopathy, non-obstructive jaundice, systemic
Types of participants inflammatory response syndrome, sepsis, or hepatocellular
carcinoma, or a combination of any of these).
We included adults with alcoholic hepatitis, diagnosed according to
• Participants with non-serious adverse events up to three
the diagnostic work-up used in the individual randomised clinical
months' follow-up after randomisation.
trial. Alcoholic hepatitis could have been established through
clinical or biochemical diagnostic criteria, or both. Exploratory analysis
We considered alcoholic hepatitis as mild if a randomised • Participants with an increase of liver enzymes as defined by the
participant had a Maddrey's score less than 32 (Maddrey's score = trialists.
4.6 × (prothrombin time – control time)(s) + serum bilirubin (mg per • Participants with a decrease of prothrombin index as defined by
dL)) (Maddrey 1978). Usually, people with mild alcoholic hepatitis the trialists.
do not have concomitant gastrointestinal bleeding. • Participants with a decrease of serum albumin as defined by the
trialists.
We considered alcoholic hepatitis as severe at any stage of the
alcoholic liver disease with the presence of spontaneous hepatic
Search methods for identification of studies
encephalopathy; or Maddrey's score of 32 or higher. We also
examined whether there was a difference in terms of initiation of Electronic searches
treatment with glucocorticosteroids in trials using the Maddrey's
We searched Cochrane Hepato-Biliary's Controlled Trials Register
score where severe alcoholic hepatitis was defined as 32 or higher.
(Gluud 2017; 18 January 2019), Cochrane Central Register of
Included trial participants diagnosed with severe alcoholic Controlled Trials (CENTRAL; 2019, Issue 1) in the Cochrane Library,
hepatitis could also manifest with hepatic encephalopathy, MEDLINE Ovid (1946 to 18 January 2019), Embase Ovid (1974 to
gastrointestinal bleeding, cirrhosis (e.g. classified with Child-Pugh 18 January 2019), LILACS, and Science Citation Index Expanded
score – Child-Pugh type C (Pugh 1973)), ascites, hepatorenal (Web of Science; 1900 to 18 January 2019) (Royle 2003). We applied
syndrome, hyponatraemia, or spontaneous bacterial peritonitis. no language or document-type restrictions. Appendix 1 shows the
search strategies with the time spans of the searches.
For studies not reporting the Maddrey's score, we used the
classifications for mild and severe alcoholic hepatitis as provided Searching other resources
by the trialists. We searched online trials registries such as ClinicalTrials.gov
(clinicaltrials.gov), European Medicines Agency (EMA;
Informed decisions.
www.ema.europa.eu), World Health Organization (WHO) table. Drawing lots, tossing a coin, shuffling cards, and throwing
International Clinical Trial Registry Platform (www.who.int/ictrp), dice were adequate if an independent person not otherwise
the Food and Drug Administration (FDA; www.fda.gov), eLibrary, involved in the study performed them.
and pharmaceutical company sources for ongoing or unpublished • Unclear risk of bias: the study authors did not specify the method
trials (last search 29 January 2019). of sequence generation.
We handsearched the reference lists of articles from the • High risk of bias: the sequence generation method was not
random. We only included such studies for assessment of harms.
computerised databases and relevant review articles.
Allocation concealment
Data collection and analysis
• Low risk of bias: the participant allocations could not have
We followed the guidelines provided in the Cochrane Handbook
been foreseen in advance of, or during, enrolment. A central
for Systematic Reviews of Interventions (Higgins 2011a), and the
and independent randomisation unit controlled allocation. The
Cochrane Hepato-Biliary Module (Gluud 2017). We performed the
investigators were unaware of the allocation sequence (e.g. if
analyses using Review Manager 5 (Review Manager 2014) and Trial
the allocation sequence was hidden in sequentially numbered,
Sequential Analysis (Thorlund 2011; TSA 2011; Wetterslev 2017).
opaque, and sealed envelopes).
We assessed the evidence according to Jakobsen and colleagues
(Jakobsen 2014). • Unclear risk of bias: the study authors did not describe the
method used to conceal the allocation so the intervention
Selection of studies allocations may have been foreseen before, or during,
enrolment.
We retrieved the full-text publications that we considered as
• High risk of bias: it is likely that the investigators who assigned
potentially eligible for inclusion after reading their titles and
the participants knew the allocation sequence. We only included
abstracts. Three review authors (CP, DV, GC) independently
such studies for assessment of harms.
reviewed the full-text publications for eligibility. The review authors
assessed each publication to determine if trial participants and the Blinding of participants and personnel
interventions administered met the inclusion criteria. We included
abstracts if there were sufficient data for analysis. We resolved • Low risk of bias: any of the following: no blinding or incomplete
disagreements by discussion or consulting any of the remaining blinding, but the review authors judged that the outcome was
review authors for arbitration. not likely to have been influenced by lack of blinding; or blinding
of participants and key study personnel ensured, and it was
Data extraction and management unlikely that the blinding could have been broken.
Three review authors (CP, DV, GC) independently completed a • Unclear risk of bias: any of the following: insufficient information
data extraction form for all included trials, agreed on among the to permit judgement of 'low risk' or 'high risk;' or the trial did not
authors in advance. Authors extracted general information on the address this outcome.
trial, such as publication title; place and year of publication; trial • High risk of bias: any of the following: no blinding or incomplete
design; inclusion and exclusion criteria; preliminary sample size blinding, and the outcome was likely to have been influenced
calculation reached or not; number of participants randomised in by lack of blinding; or blinding of key study participants and
each trial and following treatment allocation; diagnostic work-up; personnel attempted, but likely that the blinding could have
age (mean or median); sex or sex ratio; race; coinfection; type, been broken, and the outcome was likely to be influenced by
dose, and route of administration of glucocorticosteroids and their lack of blinding.
possible link with adverse events; concurrent medications used;
length of trial; and length of follow-up. Three review authors (CP, Blinded outcome assessment
DV, and GC) also extracted data on malnutrition whenever it was • Low risk of bias: any of the following: no blinding of outcome
clearly defined by the trial authors. assessment, but the review authors judged that the outcome
measurement was not likely to be influenced by lack of blinding;
The review authors resolved disagreements by discussion or asking
or blinding of outcome assessment ensured, and unlikely that
the advice of the review arbitrator (CG).
the blinding could have been broken.
Assessment of risk of bias in included studies • Unclear risk of bias: any of the following: insufficient information
to permit judgement of 'low risk' or 'high risk;' or the trial did not
Three review authors (CP, DV, and GC) independently assessed address this outcome.
the risk of bias of each included trial according to the
• High risk of bias: any of the following: no blinding of outcome
recommendations in the Cochrane Handbook for Systematic
assessment, and the outcome measurement was likely to
Reviews of Interventions (Higgins 2011b), the Cochrane Hepato-
be influenced by lack of blinding; or blinding of outcome
Biliary Module (Gluud 2017), and methodological studies (Schulz
assessment, but likely that the blinding could have been
1995; Moher 1998; Kjaergard 2001; Wood 2008; Savović 2012a;
broken, and the outcome measurement was likely to have been
Savović 2012b; Lundh 2017). We used the following definitions in
influenced by lack of blinding.
the assessment of risk of bias.
Incomplete outcome data
Allocation sequence generation
• Low risk of bias: missing data were unlikely to make treatment
• Low risk of bias: the study performed sequence generation using
effects depart from plausible values. The study used sufficient
computer random number generation or a random number
methods, such as multiple imputation, to handle missing data.

Informed decisions.
• Unclear risk of bias: there was insufficient information to assess the participants from all the glucocorticosteroid groups versus
whether missing data in combination with the method used to all participants from the placebo group(s). Had we been able to
handle missing data were likely to have induced bias on the include a cross-over trial from which we could extract data for
results. analyses, we would have used the data from the first treatment
• High risk of bias: the results were likely to be biased due to period of the cross-over trial.
missing data.
Dealing with missing data
Selective outcome reporting If dichotomous or continuous data were missing in a published
• Low risk of bias: the trial reported the following predefined report, whenever possible, we contacted the original investigators
outcomes: all-cause mortality, serious adverse events, and liver- to request the missing data.
related mortality. If the original trial protocol was available,
the outcomes were those called for in that protocol. If If trialists used intention-to-treat analysis to deal with missing data,
the trial protocol was obtained from a trials registry (e.g. we used these data in our primary analysis. Otherwise, we used the
www.clinicaltrials.gov), the outcomes sought should have been data that were available to us.
those enumerated in the original protocol if the trial protocol Dealing with missing data using sensitivity analysis
was registered before or at the time that the trial was begun. If
the trial protocol was registered after the trial was begun, those As some trials reported only per-protocol analysis results, we
outcomes were not considered reliable. included missing data by considering participants as treatment
• Unclear risk of bias: not all predefined outcomes were reported failures or treatment successes by imputing them according to the
fully, or it was unclear whether data on these outcomes were following two scenarios:
recorded or not.
• extreme-case analysis favouring the experimental intervention
• High risk of bias: one or more predefined outcomes were not ('best-worse' case scenario): none of the participants who
reported. dropped out from the experimental group experienced the
outcome, but all of the participants who dropped out from
Other bias
the control group experienced the outcome; including all
• Low risk of bias: the trial appeared free of other factors that randomised participants in the denominator;
could have put it at risk of bias. • extreme-case analysis favouring the control ('worst-best'
• Unclear risk of bias: the trial may or may not have been free of case scenario): all participants who dropped out from
other factors that could have put it at risk of bias. the experimental group, but none from the control group
• High risk of bias: there were other factors in the trial that could experienced the outcome; including all randomised participants
have put it at risk of bias. in the denominator.
Overall risk of bias For continuous outcomes (e.g. health-related quality of life), we
planned to perform a 'best-worst' case scenario analysis assuming
We judged each trial as having a low, unclear, or high risk of bias that all participants lost to follow-up in the experimental group had
based on the definitions described above. We included a bias risk an improved outcome (the group mean plus 1 standard deviation
assessment combining all domains and judged the trials to be at (SD)); and all those with missing outcomes in the control group
low risk of bias if none of the trial domains was assessed at high had a worsened outcome (the group mean minus 1 SD) (Jakobsen
or unclear risk of bias. Moreover, we considered trials with one or 2014). We also planned to perform 'worst-best' case scenario
more domains with unclear or high risk of bias as trials at overall analysis assuming that all participants lost to follow-up in the
high risk of bias. experimental group had a worsened outcome (the group mean
minus 1 SD); and all those with missing outcomes in the control
Measures of treatment effect
group had an improved outcome (the group mean plus 1 SD)
Dichotomous outcomes (Jakobsen 2014).
We used risk ratio (RR) with 95% confidence interval (CI) and Trial We performed the two sensitivity scenario analyses only for our
Sequential Analysis-adjusted CI for dichotomous outcomes. primary outcomes.
Continuous outcomes Assessment of heterogeneity
We used mean difference (MD) with 95% CI and Trial Sequential We addressed the presence of heterogeneity in both clinical and
Analysis-adjusted CI for health-related quality of life. We planned statistical ways.
to use the standardised mean difference (SMD) with 95% CI if trials
used different measures for health-related quality of life. To assess heterogeneity between the trials, we specifically
examined the degree of heterogeneity observed in the results using
Unit of analysis issues the I2 statistic (Higgins 2002). As thresholds for the interpretation
Trial participants as randomised per intervention group. In case of the I2 statistic could be misleading, we used the following
of multiple treatment groups, we considered only the trial group approximate guide for interpretation of heterogeneity provided
to which glucocorticosteroids were administered versus the group in the Cochrane Handbook for Systematic Reviews of Interventions
that received placebo or no intervention. If a trial consisted of more (Deeks 2011):
than two groups (either parallel or factorial design), we compared
• 0% to 40%: might not be important;

Informed decisions.
• 30% to 60%: may represent moderate heterogeneity*; Trial Sequential Analysis

• 50% to 90%: may represent substantial heterogeneity*; We applied Trial Sequential Analysis for both dichotomous and
• 75% to 100%: considerable heterogeneity*. continuous outcomes (Thorlund 2011; TSA 2011; Wetterslev 2017),
as cumulative meta-analyses are at risk of producing random errors
*The importance of the observed value of the I2 statistic depends on due to sparse data and repetitive testing of the accumulating data
the magnitude and direction of effects and the strength of evidence (Wetterslev 2008; Wetterslev 2017). To control random errors, we
for heterogeneity (e.g. P value from the Chi2 test, or a CI for I2 calculated the diversity-adjusted required information size (DARIS)
statistic). (i.e. the number of participants needed in a meta-analysis to detect
or reject a certain intervention effect) (Brok 2008; Wetterslev 2008;
For the heterogeneity adjustment of the required information size
Brok 2009; Thorlund 2009; Wetterslev 2009; Thorlund 2010).
in the Trial Sequential Analysis, we used diversity (D2) because
the I2 statistic used for this purpose underestimates the required In our meta-analysis, we based the DARIS for dichotomous
information size (Wetterslev 2009). outcomes on the event proportion in the control group; assumption
of a plausible relative risk reduction of 20% of the risk observed
Depending on the number of eligible trials, we planned to add
in the included trials; a risk of type I error of 1% due to more
covariates to a meta-regression model to adjust for heterogeneity.
than three outcomes, and as we decided to perform post hoc
Assessment of reporting biases analyses on mortality at end of treatment and at one year following
randomisation; a risk of type II error of 20%; and the diversity of
We drew funnel plots to assess reporting biases from the individual the included trials in the meta-analysis. For health-related quality
trials by plotting the RR on a logarithmic scale against its standard of life, we planned to estimate DARIS using a minimal relevant
error (Egger 1997; Sterne 2011). difference of 10% of the mean response observed in the control
group; the SD; alpha of 1% (Jakobsen 2014); beta of 20%; and
For dichotomous outcomes, we tested asymmetry using the
the diversity as estimated from the trials in the meta-analysis
Harbord test in cases where Tau2 was less than 0.1 (Harbord 2006),
(Wetterslev 2009). However, we did not conduct Trial Sequential
and we planned to use Rücker 2008 in cases where Tau2 was
Analysis because only one trial provided data on health-related
more than 0.1. For continuous outcomes, we planned to use the
quality of life. We also calculated and reported the Trial Sequential
regression asymmetry test (Egger 1997), and the adjusted rank
Analysis-adjusted CI (Thorlund 2011).
correlation (Begg 1994).
The underlying assumption of Trial Sequential Analysis is that
Data synthesis
testing for statistical significance may be performed each time
Meta-analysis a new trial is added to the meta-analysis. We added the trials
according to the year of publication, and, if more than one trial
We performed the meta-analyses using Review Manager 5 (Review
was published in a year, we added trials alphabetically according
Manager 2014), and according to the recommendations of the
to the last name of the first author. On the basis of the DARIS,
Cochrane Handbook for Systematic Reviews of Interventions (Deeks
we constructed the trial sequential monitoring boundaries for
2011).
benefit, harm, and futility (Wetterslev 2008; Thorlund 2011). These
We presented the results of dichotomous outcomes of individual boundaries determine the statistical inference one may draw
trials as RR with 95% CI and the results of the continuous outcomes regarding the cumulative meta-analysis that has not reached the
as MD with 95% CI and Trial Sequential Analysis-adjusted CI. DARIS; if the trial sequential monitoring boundary for benefit or
We applied both the fixed-effect model (DeMets 1987) and the harm is crossed before the DARIS is reached, firm evidence may
random-effects model (DerSimonian 1986) meta-analyses. If there be established and further trials may be superfluous. However,
were statistically significant discrepancies in the results (e.g. one if the boundaries are not crossed, it is most probably necessary
giving a significant intervention effect and the other no significant to continue doing trials in order to detect or reject a certain
intervention effect), we reported the more conservative point intervention effect. However, if the cumulative Z-curve crosses the
estimate of the two (Jakobsen 2014). The more conservative point trial sequential monitoring boundaries for futility, no more trials
estimate is the estimate closest to zero effect. If the two point may be needed.
estimates were equal, we used the estimate with the widest CI as
A more detailed description of Trial Sequential Analysis can be
our main result of the two analyses. We considered a P value of
found at www.ctu.dk/tsa/ (Thorlund 2011).
0.025 or less, two-tailed, as statistically significant if the required
information size was reached due to the three primary outcomes Subgroup analysis and investigation of heterogeneity
(Jakobsen 2014). Due to us expanding the number of analyses
conducted, we post hoc made the alpha level even lower. We used Whenever possible, we performed the following subgroup analyses
the eight-step procedure to assess if the thresholds for significance for all-cause mortality up to three months after randomisation.
were crossed (Jakobsen 2014). We presented heterogeneity using
• Trials at low risk of bias compared to trials at high risk of bias.
the I2 statistic (Higgins 2002). We presented the results of the
individual trials and meta-analyses in the form of forest plots. • Trials without for-profit funding compared to trials at risk of for-
profit funding (Lundh 2017).
Where data were only available from one trial (in our case • Trials with people with mild alcoholic hepatitis compared to
continuous data on health-related quality of life), we used trials with people with severe alcoholic hepatitis, following
Student's t-test (Student 1908). We planned to use Fisher's exact Maddrey's score lower than 32 or 32 or higher or presence of
test for dichotomous data in a single trial (Fisher 1922). hepatic encephalopathy; or as provided by the trialists.

Informed decisions.
• Trials with glucocorticosteroid dose 40 mg or less compared to problems with subgroup analyses); imprecision of results, and risk
trials with glucocorticosteroid dose more than 40 mg. of publication bias (Balshem 2011; Guyatt 2011a; Guyatt 2011b;
• Trials with people with severe alcoholic hepatitis without Guyatt 2011c; Guyatt 2011d; Guyatt 2011e; Guyatt 2011f; Guyatt
cirrhosis compared to trials with people with severe alcoholic 2011g; Guyatt 2011h; Guyatt 2013a; Guyatt 2013b; Guyatt 2013c;
hepatitis with cirrhosis. If cirrhosis is classified by Child-Pugh Mustafa 2013; Guyatt 2017).
score, then we may be able to perform additional subgroup
analyses in order to adjust for the clinical spectrum of the We defined the levels of evidence as 'high,' 'moderate,' 'low,' or 'very
disease. low.' These grades are defined as follows.
• Trials with people with severe alcoholic hepatitis without • High certainty: we are very confident that the true effect lies
hepatorenal syndrome compared to trials with people with close to that of the estimate of the effect.
severe alcoholic hepatitis with hepatorenal syndrome. • Moderate certainty: we are moderately confident in the effect
• Trials with people with severe alcoholic hepatitis without ascites estimate: the true effect is likely to be close to the estimate of the
compared to trials with people with severe alcoholic hepatitis effect, but there is a possibility that it is substantially different.
with ascites. • Low certainty: our confidence in the effect estimate is limited:
We did not perform any additional subgroup analyses to those the true effect may be substantially different from the estimate
planned in advance. of the effect.
• Very low certainty: we have very little confidence in the effect
Sensitivity analysis estimate: the true effect is likely to be substantially different
from the estimate of effect.
We planned to undertake additional sensitivity analyses to those
specified under Dealing with missing data should we have RESULTS
considered it necessary (e.g. trials published as full-paper articles,
abstracts, and unpublished trials). Description of studies
We compared our GRADE assessment of imprecision with that of See: Characteristics of included studies; and Characteristics of
Trial Sequential Analysis. excluded studies tables.
'Summary of findings' tables Results of the search

We used GRADEpro GDT 2015 to create a 'Summary of findings' We identified 1307 potentially relevant records through the
table for the following outcomes: all-cause mortality: up to three electronic searches (Figure 1). Of these, 37 records that referred
months' follow-up after randomisation; health-related quality to 16 randomised clinical trials fulfilled our inclusion criteria.
of life up to three months; serious adverse events during We found two trials published in abstract form (Mendenhall
treatment; liver-related mortality up to three months' follow- 1977; Richardet 1993), and 14 trials described as full-text paper
up after randomisation; participants with any complication up articles (Helman 1971; Porter 1971; Campra 1973; Blitzer 1977;
to three months' follow-up after randomisation; and number Maddrey 1978; Shumaker 1978; Depew 1980; Theodossi 1982;
of participants with non-serious adverse events up to three Mendenhall 1984; Bories 1987; Carithers 1989; Ramond 1992; De
months' follow-up after randomisation. The GRADE approach 2014; Thursz 2015). Our searches retrieved some quasi-randomised
appraises the certainty of a body of evidence based on the extent trials or observational studies that included administration of
to which one can be confident that an estimate of effect or glucocorticosteroids to people with alcoholic hepatitis, but the
association reflects the item being assessed. The certainty of a studies did not report data of interest to our review. We identified
body of evidence considers within-study risk of bias, indirectness no additional references by handsearching the reference lists of
of the evidence (population, intervention, control, outcomes), articles, retrieved through the computerised databases.
unexplained inconsistency (heterogeneity) of results (including

Informed decisions.
Figure 1. Study flow diagram.

Informed decisions.
We found one registered trial on clinicaltrials.gov comparing Based on the information that we collected from the published
methylprednisolone versus placebo in severe alcoholic hepatitis trial reports, three of the trials were not industry-funded (Porter
(NCT03160651). However, the trial has not yet started recruitment 1971; Ramond 1992; Thursz 2015), and the remaining 13 trials did
of participants. not report clearly if they were partly or completely funded by the
industry.
Included studies
Experimental interventions
Sixteen randomised clinical trials fulfilled our inclusion criteria
(Helman 1971; Porter 1971; Campra 1973; Blitzer 1977; Mendenhall Glucocorticosteroids (prednisolone or 6-methylprednisolone in
1977; Maddrey 1978; Shumaker 1978; Depew 1980; Theodossi equivalent dose of prednisolone) were administered orally or
1982; Mendenhall 1984; Bories 1987; Carithers 1989; Ramond 1992; parenterally at different dose regimens and different durations.
Richardet 1993; De 2014; Thursz 2015). Two were three-armed trials Twelve trials assessed oral glucocorticosteroids using prednisolone
(Mendenhall 1977; Mendenhall 1984), one trial was a randomised 40 mg or greater (Helman 1971; Mendenhall 1977; Maddrey
trial with a two-by-two factorial design (Thursz 2015), one trial was 1978; Shumaker 1978; Depew 1980; Mendenhall 1984; Bories
a cross-over trial (Richardet 1993), and the remaining were parallel, 1987; Carithers 1989; Ramond 1992; Richardet 1993; De 2014;
two-group design trials. There were 1884 participants randomised Thursz 2015). Three trials also allowed parenteral administration
in all trials. Some participants from Mendenhall 1977 (pilot trial or to participants who were not able to swallow (Shumaker
feasibility trial) continued participation in Mendenhall 1984. Three 1978; Carithers 1989; Ramond 1992). Two trials assessed oral
trials were conducted in France, one in India, two in the UK, and glucocorticosteroids using prednisolone less than 40 mg (Campra
10 in the USA (Characteristics of included studies table). All the 1973; Blitzer 1977), and in one trial the initial therapy was parenteral
trials reported the sex (65% of the participants were men) and and then it was administered orally (Porter 1971). One trial
age of the participants (range 25 years to 70 years). Four trials used only parenteral (intravenous) glucocorticosteroids (Theodossi
excluded women (Blitzer 1977; Mendenhall 1977; Mendenhall 1984; 1982).
De 2014). Eleven trials reported to have included participants at
different stages of alcoholic liver disease due to hepatitis, fibrosis, The median duration of glucocorticosteroid administration was 28
or cirrhosis (Helman 1971; Porter 1971; Campra 1973; Blitzer 1977; days with a range of three days (Theodossi 1982) to 11 weeks (De
Maddrey 1978; Depew 1980; Theodossi 1982; Mendenhall 1984; 2014): one week (Richardet 1993), three weeks (Mendenhall 1977),
Bories 1987; Ramond 1992; Thursz 2015). Most trials established four weeks (Ramond 1992; Thursz 2015), 26 days (Blitzer 1977), one
diagnosis primarily through liver biopsy. One trial included only month (Maddrey 1978; Mendenhall 1984; Bories 1987), five weeks
participants with liver cirrhosis in addition to alcoholic hepatitis (Shumaker 1978; Carithers 1989), six weeks (Helman 1971; Campra
(De 2014). The remaining trials did not provide information on the 1973; Depew 1980), 45 days (Porter 1971). Ten trials tapered the
stage of disease. All the trials included participants with recent dose of prednisolone until it was stopped (Helman 1971; Porter
history of alcohol consumption, increase of serum bilirubin, liver 1971; Campra 1973; Blitzer 1977; Mendenhall 1977; Shumaker 1978;
enzymes, prolonged prothrombin time, and participants without Depew 1980; Mendenhall 1984; Carithers 1989; De 2014).
previous treatment with glucocorticosteroids within the three
Control interventions
months before the start of the trial. Ten trials performed liver biopsy
whenever possible (Helman 1971; Porter 1971; Campra 1973; Blitzer Twelve trials used placebos that were identical in appearance to the
1977; Maddrey 1978; Shumaker 1978; Depew 1980; Bories 1987; glucocorticosteroid intervention (Helman 1971; Porter 1971; Blitzer
Ramond 1992; Thursz 2015); however, it was an inclusion criterion 1977; Mendenhall 1977; Maddrey 1978; Shumaker 1978; Depew
in only one trial, performed at admission and after treatment 1980; Mendenhall 1984; Carithers 1989; Ramond 1992; De 2014;
(Helman 1971). Thursz 2015), and four trials used no intervention (Campra 1973;
Theodossi 1982; Bories 1987; Richardet 1993).
Ten trials reported the period of trial enrolment (range of one year
to five years; median of three years) (Campra 1973; Blitzer 1977; Cointerventions
Mendenhall 1977; Maddrey 1978; Depew 1980; Mendenhall 1984;
Bories 1987; Carithers 1989; De 2014; Thursz 2015). The earliest trial Two trials administered pentoxifylline to both glucocorticosteroids
began participant recruitment in 1966 (Campra 1973), and the most and placebo intervention groups (De 2014; Thursz 2015). There
recently published trial began recruitment in 2011 and completed seemed to be no interaction between the intervention effects of
it in 2014 (Thursz 2015). pentoxifylline and glucocorticosteroids (De 2014; Thursz 2015).
Three trials followed participants up to one year (Mendenhall Outcomes

1984; De 2014; Thursz 2015). The remaining trials followed their The Characteristics of included studies tables details the outcomes
participants to the moment of discharge from the hospital or until reported in the individual trials. Five trials reported on outcomes
death occurred, with a median duration of follow-up of 63 days with a follow-up period up to three months after randomisation
(range 28 to 120). (Helman 1971; Mendenhall 1977; Bories 1987; De 2014; Thursz
2015). Twelve trials reported on outcomes at the end of treatment
We could extract data for analysis from all 16 trials but one or at the moment of discharge from the hospital (Helman 1971;
(Richardet 1993). We contacted Richardet and colleagues in Porter 1971; Campra 1973; Blitzer 1977; Maddrey 1978; Shumaker
2006, but received no reply. In the remaining 15 trials, 182 1978; Depew 1980; Theodossi 1982; Bories 1987; Carithers 1989;
participants had mild alcoholic hepatitis and 1679 had severe Ramond 1992; Richardet 1993). Three trials exceeded the 12-month
alcoholic hepatitis. The analyses of the 15 trials accounted for follow-up period (Mendenhall 1984; De 2014; Thursz 2015).
927 participants randomised to glucocorticosteroids, and 934
participants randomised to placebo or no intervention.

Informed decisions.
Only one trial reported health-related quality of life, using the Blinding
European Quality of Life – 5 dimensions (EQ-5D) score registered to
Three trials were at high risk of performance bias as they were
Eudra CT 2009-013897-42 and ISRCTN 88782125 and it was reported
open-label trials, without blinding of participants or investigators
in all the groups at three months' follow-up after randomisation,
(Campra 1973; Theodossi 1982; Bories 1987), and one trial used
and at one year (Thursz 2015; see Notes in Characteristics of
placebo, but there was no description of it and we judged the risk
included studies table).
of bias as unclear (Richardet 1993). Twelve trials were blinded,
None of the trials provided usable data for meta-analyses of our using identical placebo, and hence, at low risk of bias (Helman
exploratory outcomes. 1971; Porter 1971; Blitzer 1977; Mendenhall 1977; Maddrey 1978;
Shumaker 1978; Depew 1980; Mendenhall 1984b: Carithers 1989;
For further details on trial characteristics, see Characteristics of Ramond 1992; De 2014; Thursz 2015).
included studies table.
We assessed four trials at low risk of detection bias (Porter 1971;
Excluded studies Shumaker 1978; De 2014; Thursz 2015), one trial at high risk
of bias (Carithers 1989), and the remaining 11 trials as unclear
We excluded 29 publications from the final assessment with the
risk of detection bias (Helman 1971; Campra 1973; Blitzer 1977;
reasons for their exclusion provided in the Characteristics of
Mendenhall 1977; Maddrey 1978; Depew 1980; Theodossi 1982;
excluded studies table.
Mendenhall 1984; Bories 1987; Ramond 1992; Richardet 1993).
Among the excluded studies were two trials that used a nutritional
Incomplete outcome data
intervention in the control group (Lesesne 1978; Cabré 2000).
Although nutritional intervention as an overall intervention does We classed four trials at high risk of attrition bias because they did
not seem to influence all-cause mortality or serious adverse events not account for participants with missing outcomes (Porter 1971;
(Feinberg 2017), including the Cabré 2000 and Lesesne 1978 trials in Blitzer 1977; Theodossi 1982; Thursz 2015 (the latter regarding
our review would not have affected our results noticeably because one-year follow-up results)). Twelve trials were assessed as having
these trials were small and had very few events. low risk of attrition bias (Helman 1971; Campra 1973; Mendenhall
1977; Maddrey 1978; Shumaker 1978; Depew 1980; Mendenhall
Risk of bias in included studies 1984; Bories 1987; Carithers 1989; Ramond 1992; De 2014; Thursz
2015 (the latter regarding follow-up to end of treatment and up to
Allocation
three-month follow-up)). We judged one trial at unclear risk of bias
Random sequence generation (Richardet 1993).
We assessed the random sequence generation as low risk of bias in Selective reporting
eight trials (Porter 1971; Campra 1973; Blitzer 1977; Maddrey 1978;
Carithers 1989; Ramond 1992; De 2014; Thursz 2015), and as unclear There were three trials at high risk of bias (Helman 1971;
in the remaining trials (Helman 1971; Mendenhall 1977; Shumaker Mendenhall 1977; Mendenhall 1984), and one trial at unclear risk
1978; Depew 1980; Theodossi 1982; Mendenhall 1984; Bories 1987; of bias (Richardet 1993). We found a registered protocol for only
Richardet 1993). one trial (Thursz 2015). The remaining 11 trials reported all-cause
mortality, serious adverse events, and liver-related mortality. Thus,
Allocation concealment 12 trials were at low risk of selective reporting bias.
We assessed allocation concealment as low risk of bias in ten Other potential sources of bias
trials (Helman 1971; Porter 1971; Campra 1973; Blitzer 1977;
Shumaker 1978; Theodossi 1982; Mendenhall 1984; Carithers 1989; We identified no other biases in 15 of the included trials. One trial
Ramond 1992; Thursz 2015), and as unclear in the remaining was published as an abstract; we assessed this domain at unclear
trials (Mendenhall 1977; Maddrey 1978; Depew 1980; Bories 1987; risk of other potential source of bias (Richardet 1993).
Richardet 1993; De 2014).
Overall risk of bias
We judged all trials but one (Thursz 2015) at high risk of bias. Figure
2 and Figure 3 show our assessment of risk of bias of the published
trial reports (Characteristics of included studies table).

Informed decisions.
Figure 2. Risk of bias graph: review authors' judgements about each risk of bias domain presented as percentages
across all included studies.

Informed decisions.
Figure 3. Risk of bias summary: review authors' judgements about each risk of bias domain for each included study.

Informed decisions.
Effects of interventions all-cause mortality (random-effects RR 0.90, 95% CI 0.70 to 1.15;

participants = 1861; trials = 15; I2 = 45% (moderate heterogeneity;
See: Summary of findings for the main comparison Analysis 1.1). We rated the certainty of the evidence as low
Glucocorticosteroids for people with alcoholic hepatitis (Summary of findings for the main comparison).
Primary outcomes We observed a similar result with the Trial Sequential Analysis
All-cause mortality showing that the cumulative Z-curve did not cross the trial
sequential monitoring boundaries for benefit or harm, nor enter
Up to three months following randomisation
the trial sequential monitoring area for futility in order to include
In total, 258/927 (27.8%) participants in the glucocorticosteroid an intervention effect of 20% relative risk reduction (Figure 4). The
group died versus 279/934 (29.9%) participants in the control Trial Sequential analysis-adjusted CI was 0.36 to 2.32.
group. There was no evidence of effect of glucocorticosteroids on
Figure 4. All-cause mortality up to three months after randomisation. Fifteen trials provided data. The diversity-
adjusted required information size (DARIS) was calculated based on all-cause mortality of 30% in the control group;
relative risk reduction (RRR) in the glucocorticosteroid group of 20%; type I error of 1%; and type II error of 20%
(80% power). Trial diversity was 62%. The required information size was 6734 participants. The cumulative Z-curve
(blue line) did not cross the trial sequential monitoring boundaries for benefit or harm (red inward sloping lines)
and did not enter the trial sequential monitoring area for futility (inner-wedge with red outward sloping lines). The
green dotted lines show the conventional boundaries of the naive alpha of 5% equal to Z-scores of +1.96 and –1.96.
Visual inspection of the funnel plot suggested publication bias or

small-trial bias on all-cause mortality, but when using the Harbord
2006 test, we found no evidence of bias (P = 0.31) (Figure 5).

Informed decisions.
Figure 5. Funnel plot of comparison 1. Glucocorticosteroids versus no intervention/placebo, outcome 1.1 all-cause
mortality.
'Best-worst' case scenario analysis Our Trial Sequential Analysis assessment of imprecision coincided
The 'best-worst' case scenario analysis on mortality up to three with assessment of imprecision with GRADE for all-cause mortality:
months after randomisation produced two different results. While three-months following randomisation.
there was no evidence of effect of glucocorticosteroids with the At the end of treatment (post hoc analysis)
random-effects model (RR 0.82, 95% CI 0.64 to 1.05; I2 = 47%), there
was evidence of beneficial effect with the fixed-effect model (RR Treatment lasted for a median of 28 days (range 3 days to 12 weeks).
0.74, 95% CI 0.65 to 0.84; participants = 1861; trials = 15; I2 = 47%; In total, 162/907 (17%) participants in the glucocorticosteroid group
Analysis 3.1). Heterogeneity in both analyses was moderate. died versus 202/917 (22%) participants in the control group. There
was no evidence of effect of glucocorticosteroids on all-cause
'Worst-best' case scenario analysis mortality (random-effects RR 0.87, 95% CI 0.66 to 1.15; participants
The 'worst-best' case scenario analysis on mortality up to three = 1824; trials = 14; I2 = 42%; moderate heterogeneity; Analysis 1.1.1).
months after randomisation produced two different results. While We rated the certainty of the evidence as low (not presented in
there was no evidence of effect of glucocorticosteroids with the Summary of findings for the main comparison).
random-effects model (RR 0.97, 95% CI 0.73 to 1.29; I2 = 62%), there We observed a similar result with the Trial Sequential Analysis
was evidence of a harmful effect with the fixed-effect model (RR showing that the cumulative Z-curve did not cross the trial
1.21, 95% CI 1.06 to 1.37; I2 = 62%; Analysis 3.2). sequential monitoring boundaries for benefit or harm, and did not
enter the trial sequential monitoring area for futility in order to
exclude an intervention effect of 20% RRR (Figure 6). The Trial
Sequential Analysis-adjusted CI was CI 0.29 to 2.68.

Informed decisions.
Figure 6. All-cause mortality at the end of treatment (median 28 days (range 3 days to 12 weeks) (post hoc
analysis). Fourteen trials provided data. The diversity-adjusted required information size (DARIS) was calculated
based on all-cause mortality of 22% in the control group; relative risk reduction (RRR) in the glucocorticosteroid
group of 20%; type I error of 1%; and type II error of 20% (80% power). Trial diversity was 59%. The required
information size was 9242 participants. The cumulative Z-curve (blue line) did not cross the trial sequential
monitoring boundaries for benefit or harm (red inward sloping lines) and did not enter the trial sequential
monitoring area for futility (inner-wedge with red outward sloping lines). The green dotted lines show the
conventional boundaries of the naive alpha of 5% equal to Z-scores of +1.96 and –1.96.
Visual inspection of the funnel plot suggested publication bias or Thursz 2015). In total, 274/668 (41%) participants in the
small-trial bias on all-cause mortality at the end of treatment, but glucocorticosteroid group died versus 265/664 (40%) participants
when using the Harbord 2006 test, we found no evidence of bias (P in the control group. There was no evidence of effect of
= 0.84) (Figure 5). glucocorticosteroids on all-cause mortality (random-effects RR
1.03, 95% CI 0.91 to 1.17; participants = 1343; trials = 3; I2 = 0%;
A sensitivity analysis of full-text articles (RR 0.85, 95% CI 0.64 to no heterogeneity among the trials; Analysis 1.1.3). We rated the
1.11; participants = 1795; studies = 13; I2 = 41%) and abstract (RR certainty of the evidence as moderate (not presented in Summary
2.83, 95% CI 0.61 to 13.06; participants = 29; studies = 1; I2 = 0%) of findings for the main comparison).
did not affect the overall result of mortality at the end of treatment
(analysis not shown). We observed a similar result with the Trial Sequential Analysis
showing that the cumulative Z-curve entered the area of futility,
One year following randomisation (post hoc analysis) which excludes an intervention effect of 20% RRR (Figure 7). The
Three of the included trials provided data on all-cause mortality Trial Sequential analysis-adjusted CI was CI 0.85 to 1.25.
one year following randomisation (Mendenhall 1984; De 2014;

Informed decisions.
Figure 7. All-cause mortality up to 1 year (post hoc analysis). Three trials provided data. The diversity-adjusted
required information size (DARIS) was calculated based on mortality in the control group of 40%; relative risk
reduction (RRR) of 20% in the glucocorticosteroid group; type I error of 1%; and type II error of 20% (80% power).
Trial diversity was 0%. The required information size was 1695 participants. The cumulative Z-curve (blue line)
did not cross the trial sequential monitoring boundaries for benefit or harm (red inward sloping lines). The
cumulative Z-curve crossed the inner-wedge futility line (red outward sloping lines). The green dotted lines show
the conventional boundaries of the naive alpha of 5% equal to Z-scores of +1.96 and –1.96.
Subgroup analysis and investigation of heterogeneity: all-cause ((RR 1.03, 95% CI 0.84 to 1.26; participants = 1103; Analysis 2.1.1)
mortality up to three months after randomisation and the remaining 14 trials at high risk of bias ((RR 0.86, 95% CI 0.63
to 1.17; participants = 758; studies = 14; I2 = 48%; Analysis 2.1.2).
Trials at low risk of bias compared to trials at high risk of bias
Thursz 2015 was the only trial at low risk of bias. There was no Trials with people with mild alcoholic hepatitis compared to trials
significant difference (P = 0.32) between the subgroups of trials with severe alcoholic hepatitis, following Maddrey's score lower
than 32 or 32 or higher or presence of hepatic encephalopathy; or as
including one trial at low risk of bias (RR 1.03, 95% CI 0.84 to 1.26;
provided by the trialists
participants = 1103; studies = 1; I2 = 0%; Analysis 2.1.1; P = ) and the
remaining 14 trials at high risk of bias (RR 0.86, 95% CI 0.63 to 1.17; There was no significant difference (P = 0.75) between the
participants = 758; studies = 14; I2 = 48%; Analysis 2.1.2). subgroups (mild alcoholic hepatitis: RR 1.02, 95% CI 0.58 to 1.80;
participants = 182; trials = 4; I2 = 0%; Analysis 2.3.1) and severe
Trials without for-profit funding compared to trials at risk of for-profit alcoholic hepatitis (RR 0.92, 95% CI 0.73 to 1.16; participants = 1679;
funding trials = 14; I2 = 37%; Analysis 2.3.2).
Thursz 2015 was the only trial which seemed not to have received
industry funding. There was no significant difference (P = 0.32)
between the subgroups of trials including one trial at low risk of bias

Informed decisions.
Trials with glucocorticosteroid dose 40 mg or less compared to trials = 729; trials = 13; I2 = 48%; Analysis 2.7.1). In addition, two trials
with glucocorticosteroid dose more than 40 mg did not clearly describe the presence of ascites (Mendenhall 1977;
There was no significant difference (P = 0.22) between the Thursz 2015).
subgroups of the trials with glucocorticosteroid dose less than
Health-related quality of life
or equal to 40 mg (RR 0.75, 95% CI 0.50 to 1.14; participants
= 1547; trials = 10; I2 = 58%; Analysis 2.4.1) and trials with Up to three months
glucocorticosteroid dose more than 40 mg (RR 1.02, 95% CI 0.79 to
Only one trial reported quality of life at a follow-up period of up
1.30; participants = 314; trials = 5; I2 = 0%; Analysis 2.4.2).
to three months, using responses to the European Quality of Life
Trials with people with severe alcoholic hepatitis without cirrhosis – 5 Dimensions – 3 Levels (EQ-5D-3L) (Thursz 2015). We applied
compared to trials with people with severe alcoholic hepatitis with the Student's t-test for the glucocorticosteroids versus the placebo
cirrhosis group. We observed no difference between the two groups (MD
–0.04 points, 95% CI –0.11 to 0.03; Analysis 1.2). We rated the
There was no significant difference (P = 0.83) between the
certainty of the evidence as low (Summary of findings for the main
subgroups of the trials with severe alcoholic hepatitis without
comparison). We did not perform Trial Sequential Analysis.
cirrhosis (RR 0.79, 95% CI 0.18 to 3.48; participants = 123; trials = 3;
I2 = 77%; Analysis 2.5.1) and trials with people with severe alcoholic Up to one year
hepatitis with cirrhosis (RR 0.92, 95% CI 0.74 to 1.16; participants =
1738; studies = 12; I2 = 35%; Analysis 2.5.2). Only one trial reported quality of life at a follow-up period of
up to one year, using responses to the EQ-5D-3L (Thursz 2015).
As only two trials classified cirrhosis by Child-Pugh score (Bories We applied the Student's t-test for the glucocorticosteroids versus
1987; De 2014), and we did not know what classification system the placebo group. We observed no difference between the two
the remaining trials had used, we could not perform a subgroup groups (MD 0.00 points; 95% CI –0.11 to 0.10; Analysis 1.2). We rated
analysis in order to adjust for the clinical spectrum of the disease. the certainty of the evidence as low (not presented in Summary
of findings for the main comparison). We did not perform Trial
Trials with people with severe alcoholic hepatitis without hepatorenal Sequential Analysis.
syndrome compared to trials with people with severe alcoholic
hepatitis with hepatorenal syndrome As the data for health-related quality of life came from one and the
There was no significant difference (P = 0.64) between the same trial, we could not perform sensitivity analyses.
subgroups of the trials with people with severe alcoholic hepatitis
Serious adverse events during treatment
without hepatorenal syndrome (RR 1.00, 95% CI 0.85 to 1.17;
participants = 1382; studies = 8; I2 = 0%; Analysis 2.6.1) compared to Fifteen trials reported number of participants with serious adverse
trials with people with severe alcoholic hepatitis with hepatorenal events during treatment. In total, 361/927 (38%) participants in
syndrome (RR 0.56, 95% CI 0.05 to 6.49; participants = 129; studies the glucocorticosteroid group had serious adverse events during
= 2; I2 = 88%; Analysis 2.6.2). Five trials did not clearly describe the treatment versus 338/934 (36%) participants in the control group.
presence of hepatorenal syndrome (Blitzer 1977; Mendenhall 1977; There was no evidence of effect of glucocorticosteroids on the
Mendenhall 1984; Bories 1987; Ramond 1992). occurrence of serious adverse events (random-effects RR 1.05, 95%
CI 0.85 to 1.29; participants = 1861; trials = 15; I2 = 36%; moderate
Trials with people with severe alcoholic hepatitis without ascites heterogeneity; Analysis 1.3). We rated the certainty of the evidence
compared to trials with people with severe alcoholic hepatitis with
as very low (Summary of findings for the main comparison).
ascites
As we did not have data on trials with participants not having We observed a similar result with the Trial Sequential Analysis
ascites, we could analyse only the subgroup of trials including showing that the cumulative Z-curve entered the area of futility
participants with ascites (RR 0.82, 95% CI 0.60 to 1.12; participants which excludes an intervention effect of 20% RRR (Figure 8). The
Trial Sequential analysis-adjusted CI was 0.60 to 1.82.

Informed decisions.
Figure 8. Serious adverse events during treatment. There are 15 trials providing data. The diversity-adjusted
required information size (DARIS) was calculated based on an incidence rate of serious adverse events in the control
group of 36%; relative risk reduction (RRR) of 20% in the glucocorticosteroid group; type I error of 1%; and type
II error of 20% (80% power). Trial diversity was 70%. The required information size was 6566 participants. The
cumulative Z-curve (blue line) did not cross the trial sequential monitoring boundaries for benefit or harm (red
inward sloping lines), but it entered the trial sequential monitoring area for futility (inner-wedge futility line
red outward sloping lines) indicating that sufficient information was provided. The green dotted lines show the
conventional boundaries of the naive alpha of 5% equal to Z-scores of +1.96 and –1.96.
Table 1 shows the number of participants with the most often effect model: RR 0.99, 95% CI 0.89 to 1.11; participants = 1861; I2 =
occurring serious adverse events in 14 included trials; mortality was 28%; not important heterogeneity; Analysis 4.1).
not included. Table 2 presents the most often occurring serious
adverse events in Thursz 2015 because this trial did not specify the 'Worst-best' case scenario analysis
individual number of participants with a serious adverse event. While there was evidence of a harmful effect of glucocorticosteroids
with the fixed-effect model (RR 1.18, 95% CI 1.05 to 1.31;
We constructed a funnel plot for publication bias, and using the participants = 1861; I2 = 38%), there was no evidence of effect of
Harbord 2006 test, we found no evidence of reporting bias (P = 0.63). glucocorticosteroids with the random-effects model (RR 1.11, 95%
'Best-worst' case scenario analysis CI 0.91 to 1.36; I2 = 38%; Analysis 4.2).
There was no evidence of effect of glucocorticosteroids on serious Our Trial Sequential Analysis assessment of imprecision coincided
adverse events during treatment, with neither of the models with assessment of imprecision with GRADE for serious adverse
(random-effects model: RR 1.00, 95% CI 0.83 to 1.21; participants events during treatment.
= 1861; studies = 15; I2 = 28%; not important heterogeneity; fixed-

Informed decisions.
A sensitivity analysis of full-text articles (RR 1.03, 95% CI 0.84 to group. There was no evidence of effect of glucocorticosteroids on
1.27; participants = 1832; studies = 14; I2 = 36%) and abstract (RR liver-related mortality (random-effects RR 0.89, 95% CI 0.69 to 1.14;
2.83, 95% CI 0.61 to 13.06; participants = 29; studies = 1; I2 = 0%) did participants = 1861; trials = 15; I2 = 46%; moderate heterogeneity;
not affect the serious adverse events during treatment (analysis not Analysis 1.4). We rated the certainty of the evidence as very low
shown). (Summary of findings for the main comparison).
Secondary outcomes We observed a similar result with the Trial Sequential Analysis
showing that the cumulative Z-curve did not cross the trial
Liver-related mortality up to three months' follow-up after
sequential monitoring boundaries for benefit or harm, nor enter
randomisation
In total, 257/927 (27.7%) participants in the glucocorticosteroid an intervention effect of 20% RRR (Figure 9). The Trial Sequential
group died versus 279/934 (29.9%) participants in the control analysis-adjusted CI was 0.32 to 2.45.
Figure 9. Liver-related mortality up to three months after randomisation. Fifteen trials provided data. The
diversity-adjusted required information size (DARIS) was calculated based on liver-related mortality of 30% in
the control group; relative risk reduction (RRR) in the glucocorticosteroid group of 20%; type I error of 1%; and
type II error of 20% (80% power). Trial diversity was 68%. The required information size was 8059 participants.
The cumulative Z-curve (blue line) did not cross the trial sequential monitoring boundaries for benefit or harm
(red inward sloping lines) and did not enter the trial sequential monitoring area for futility (inner-wedge with red
outward sloping lines). The green dotted lines show the conventional boundaries of the naive alpha of 5% equal to
Z-scores of +1.96 and –1.96.

Informed decisions.
Our Trial Sequential Analysis assessment of imprecision coincided participants = 1861; I2 = 42%; moderate heterogeneity; Analysis 1.5).
with assessment of imprecision with GRADE for liver-related We rated the certainty of the evidence as very low, mainly due
mortality up to three months following randomisation. to within-study bias, inconsistency, and imprecision (Summary of
findings for the main comparison).
Participants with any complication up to three months' follow-
up after randomisation We observed a similar result with the Trial Sequential Analysis
showing that the cumulative Z-curve did not cross the trial
In total, 440/927 (47%) participants in the glucocorticosteroid
sequential monitoring boundaries for benefit or harm but it crossed
group had one or more complications versus 414/934 (44%)
participants in the control group. There was no evidence of
an intervention effect of 20% RRR (Figure 10). The Trial Sequential
effect of glucocorticosteroids on the number of participants with
analysis-adjusted CI was 0.67 to 1.63.
any complications (random-effects RR 1.04, 95% CI 0.86 to 1.27;
Figure 10. Any complications up to three months' follow-up after randomisation. Fifteen trials provided data.
The diversity-adjusted required information size (DARIS) was calculated based on any complications of 44% in the
control group; relative risk reduction (RRR) in the glucocorticosteroid group of 20%; type I error of 1%; and type
II error of 20% (80% power). Trial diversity was 75%. The required information size was 5887 participants. The
cumulative Z-curve (blue line) did not cross the trial sequential monitoring boundaries for benefit or harm (red
inward sloping lines). The cumulative Z-curve crossed the inner-wedge futility line (red outward sloping lines). The
green dotted lines show the conventional boundaries of the naive alpha of 5% equal to Z-scores of +1.96 and –1.96.
Our Trial Sequential Analysis assessment of imprecision coincided

with assessment of imprecision with GRADE for number of
participants with any complication up to three months' follow-up
after randomisation.
Informed decisions.
Participants with non-serious adverse events up to three heterogeneity; Analysis 1.6). We rated the certainty of the evidence
months' follow-up after randomisation as very low to low (Summary of findings for the main comparison).
Only four trials reported non-serious adverse events such as We observed a similar result with the Trial Sequential Analysis
Cushingoid symptoms, vertigo, and fungal lesions. There was showing that the cumulative Z-curve did not cross the trial
no evidence of effect of glucocorticosteroids on number of sequential monitoring boundaries for benefit or harm, nor did it
participants with non-serious adverse events (random-effects RR enter the trial sequential monitoring area for futility in order to
1.99, 95% CI 0.72 to 5.48; participants = 160; trials = 4; I2 = 0%; no include an intervention effect of 50% RRR (Figure 11). The Trial
Sequential Analysis-adjusted CI was 0.01 to 249.60.
Figure 11. Non-serious adverse events up to three months after randomisation. Four trials provided data. The
diversity-adjusted required information size (DARIS) was calculated based on non-serious adverse events of 5%
in the control group; relative risk reduction (RRR) in the glucocorticosteroid group of 50%; type I error of 1%; and
type II error of 20% (80% power). Trial diversity was 0%. The required information size was 2698 participants.
The cumulative Z-curve (blue line) did not cross the trial sequential monitoring boundaries for benefit or harm
(red inward sloping lines) and did not enter the trial sequential monitoring area for futility (inner-wedge with red
outward sloping lines). The green dotted lines show the conventional boundaries of the naive alpha of 5% equal to
Z-scores of +1.96 and –1.96.
Our Trial Sequential Analysis assessment of imprecision coincided Exploratory outcomes at the end of treatment
with assessment of imprecision with GRADE for number of people
No trial reported on number of participants with change of level
with non-serious adverse events up to three months following
of liver enzymes, prothrombin index, or serum albumin at the
randomisation.
end of treatment. This is why we could not perform the planned
exploratory analyses. Instead, post hoc, we decided to present in
Informed decisions.
a tabular way the extracted information on level of liver enzymes This review is applicable to people with alcoholic hepatitis at
reported in the trials by Campra 1973; Maddrey 1978; Theodossi different stages of the disease. Our meta-analyses and Trial
1982; and Carithers 1989 (Appendix 2); prothrombin index or Sequential Analyses seem to provide no evidence of benefit of
international normalised ratio reported in the trials by Campra glucocorticosteroids on all-cause mortality at one-year follow-up
1973; Maddrey 1978; Theodossi 1982; Carithers 1989; Ramond 1992 after randomisation. It is also unlikely that glucocorticosteroids
(Appendix 3); and level of serum albumin (and bilirubin post hoc) may have a beneficial effect on mortality at the end of treatment
reported in the trials by Campra 1973; Maddrey 1978; Depew 1980; and three months following randomisation; however, due to mainly
Theodossi 1982; Carithers 1989; and Ramond 1992 (Appendix 4; imprecision (the CI crossed the clinical decision threshold between
Appendix 5). recommending and not recommending treatment and the required
number of participants was far from reached), we could not exclude
'Summary of findings' table the possibility of a short-term beneficial or harmful effect. We could
We presented the key results on the outcomes all-cause mortality, not say if glucocorticosteroids may have influenced infection and
health-related quality of life, serious adverse events, liver-related gastrointestinal bleeding as we had no data for meta-analysis.
mortality, all complications, and non-serious adverse events in However, Thursz and colleagues' analysis showed an increase
Summary of findings for the main comparison. We assessed in the number of these complications in treated participants
the evidence as being very low for all listed outcomes but (Thursz 2015). The only worst-best sensitivity analysis for all-
health-related quality of life for which the evidence was low. We cause mortality and serious adverse events showed a tendency of
downgraded the evidence because of within-study risk of bias, harmful effect of glucocorticosteroids compared to the best-worse
inconsistency of the data, imprecision, and publication bias. We sensitivity analysis showing no difference in effect.
presented the results obtained at predefined primary time points.
Quality of the evidence
DISCUSSION The certainty of the evidence reflects only the quality of the
included trials, and this is why we could not be certain in our
Summary of main results conclusions. We judged the overall certainty of evidence as low for
We included 16 randomised clinical trials comparing health-related quality of life to very low for all outcomes except
glucocorticosteroids versus placebo or no intervention in people for all-cause mortality at one year after randomisation, for which
with alcoholic hepatitis. Fifteen trials provided data for analyses. the certainty of the evidence was moderate (not presented in
Our meta-analyses showed no beneficial or detrimental effects of Summary of findings for the main comparison). The randomisation
glucocorticosteroids on any of our outcomes. In general, serious procedures were insufficiently reported in 15 of the trials. In
and non-serious adverse events as well as complications were addition to downgrading the trials for within-study risk of bias, we
poorly reported or the information was unclear, and hence, these also downgraded the trials for imprecision of effect estimates due
analyses may be subject to outcome reporting bias (Ioannidis to the number of participants included in the trials (all but one of
2009). Trial Sequential Analyses showed similar results. Based the 14 trials had fewer than 400 participants), and for inconsistency
on methodological concerns, we classified the certainty of the of the results (there was wide variation in the effect estimates
evidence as low for health-related quality of life, and very low for across the trials; there was little overlap of CIs associated with
all the remaining primary and secondary outcomes. We assessed the effect estimates; and we assessed heterogeneity of the data as
the certainty of evidence for all-cause mortality at one-year follow- moderate with I2 statistics of 36% to 46%, which could be explained
up (post hoc analysis) as moderate. As only one trial was at low risk with selection bias). We found no statistical evidence of publication
of bias, it is more likely that that the trials at high risk of bias were bias or small-study bias.
overestimating benefits and overlooking harms.
In spite of the certainty of the evidence being very low or low,
Overall completeness and applicability of evidence we are reasonably confident in our recommendations regarding
implications for practice and for research. This ensues from
The trial participants varied according to severity of alcoholic our analysis results and is based on the knowledge that trials
hepatitis and the trials were published between 1971 and 2015. at high risk of bias overestimate benefits and underestimate
However, only 1861 participants were included. During this time harms. Therefore, we found no supporting evidence for using
period, glucocorticosteroid interventions varied regarding dose glucocorticosteroids in clinical practice. There is definitely a need
and duration. The small number of trials and trial participants, with for more transparent reporting of individual participant data
the exception of Thursz 2015, the poor trial design and reporting, (NTAWG 2015; Garattini 2016).
all make the results of our review inconclusive. The high risk of bias
of almost all trials undermined the precision of our meta-analyses Potential biases in the review process
results.
The strengths of our review are that we have conducted our review
We were unable to assess if ethnicity had any influence on our following the recommendations of Cochrane Hepato-Biliary and
results, as data were either lacking or insufficient. The same the Cochrane Handbook for Systematic Reviews of Interventions
applied for the nutritional status of the participants, as only one (Higgins 2011c; Gluud 2017). We included only randomised clinical
trial reported on it (Mendenhall 1984). Mathurin and coworkers trials in our review. This creates a bias towards focusing on
proposed that people with alcoholic hepatitis with Maddrey's benefits as short-term randomised trials often overlook harms.
score of at least 32 should likely benefit from glucocorticosteroids We attempted to minimise possible selection biases by using
(Mathurin 2011). However, we found no significant effect of a comprehensive search strategy. We combined searches in
glucocorticosteroids in this subgroup of trial participants. electronic databases with extensive manual searches. In addition,
we also searched conference proceedings and abstract books,

Informed decisions.
irrespective of language. We think it is unlikely that we have missed Our systematic review of pair-wise comparison randomised clinical
any published trials, but we cannot exclude the possibility that trials is in agreement with the meta-analysis by Buzzetti 2017. In
we have missed unpublished trials. Visual inspection of the funnel this network meta-analysis, the authors found no significant effects
plots suggests publication bias or small-study bias on all-cause of glucocorticosteroids on mortality at maximal follow-up and up
mortality at the end of treatment and following three months after to 90 days of follow-up.
randomisation in contrast to the statistical result with Harbord
2006 test (Figure 5). We wrote to pharmaceutical companies and Our review now includes 1861 participants. The Thursz 2015
regulatory authorities. We made extensive attempts to avoid risk of trial included 1103 participants and found "a reduction in the
system and random errors. We assessed the evidence with GRADE 28-day mortality in the prednisolone-treated group on logistic
approach. regression model analysis, but there was not clear evidence of
benefit, sustained beyond this point." Mathurin 2011 performed
Limitations of our review were the small number of trials and "analysis of individual data from five randomised clinical trials
the small total number of participants. Having in mind that which showed that corticosteroids significantly improved 28-
hepatitis C viral disease was discovered as late as 1989, we day survival in patients with severe alcoholic hepatitis." In
might have run the risk that the included trials initiated before our present aggregate meta-analysis, based on the certainty
1989 did not include participants with only alcoholic hepatitis of evidence, we could not determine whether there was an
(Houghton 2009). Furthermore, our results were hampered by the effect or not of glucocorticosteroids on mortality at 'end of
quality of the included trials as well as imprecision and severe treatment,' which is quite close to 28 days. The review by
inconsistency. Even though all trials provided data on mortality, Louvet 2018 (see Why it is important to do this review
data on other serious adverse events and complications were section), assessed the effects of corticosteroids versus placebo or
rarely reported, which calls into question the reliability of the two control, corticosteroids versus pentoxifylline, corticosteroids plus
latter analyses. Only one trial reported quality of life. Moreover, pentoxifylline versus corticosteroids plus placebo or control, and
by including primarily randomised clinical trials we have focused pentoxifylline versus placebo in four meta-analyses. However, the
on potential beneficial effects and overlooked the many known number of participants with severe alcoholic hepatitis providing
harms connected with the administration of glucocorticosteroids. individual participants' data from the six included in the meta-
Again, these flaws in our review make us suspect that benefits are analysis trials, comparing corticosteroids versus placebo or control,
overestimated and harms are underestimated. was too small to draw a firm conclusion on the beneficial or
harmful effects of glucocorticosteroids. In addition, the control
When conducting our Trial Sequential Analyses, we used plausible intervention of two of the included six studies was nutrition or
parameters to calculate our required information sizes. However, antioxidants, which did not compare well with the placebo group
we only used 80% power (beta = 20%). Had we used 90% power of participants. The conclusions Louvet and colleagues made was
(beta = 10%) or less, which is relevant in meta-analyses where that "corticosteroids used to reduce risk of death within 28 days
one does not want to discharge a potentially relevant intervention, of treatment, but not in the following six months. This loss of
then we would have obtained larger required information sizes efficacy over time indicates a need for new therapeutic strategies to
and wider Trial Sequential Analyses-adjusted CIs (Garattini 2016; improve medium-term outcomes." Louvet and colleagues did not
Castellini 2017). Accordingly, the imprecision may be worse than assess the risk of bias and the quality of the included trials which
signalled by our analyses. adds further to the unreliability of their conclusions.
Agreements and disagreements with other studies or Clinical guidelines recommend prescribing glucocorticosteroids
reviews as follows: AASLD 2010 reads: "Patients with severe disease
(Maddrey's Discriminant Function (MDF) score of ≥ 32, with or
The meta-analysis by Christensen 1995 found no effect of
without hepatic encephalopathy) and lacking contraindications
glucocorticosteroids versus placebo on mortality. The review
to steroid use should be considered for a four-week course
included data from 13 trials with 659 participants randomised.
of prednisolone (40 mg/day for 28 days, typically followed by
Rambaldi 2008 updated the meta-analysis by Christensen 1995,
discontinuation or a 2-week taper) (Class I, level A)" and EASL 2012
adding two more trials with 62 participants randomised. Hence,
reads: "First-line therapy in patients with severe alcoholic hepatitis
Rambaldi 2008 concluded that depending on the estimation of
includes corticosteroids or, in case of ongoing sepsis, pentoxifylline
the information size, their review lacked another 1000 to 2000
(Recommendation B1)." In the absence of active infection, EASL
participants randomised to glucocorticosteroids versus placebo in
2018 suggests the use of corticosteroids (prednisolone 40 mg/day
order to be able to either demonstrate or reject a clinically relevant
or methylprednisolone 32 mg/day) for people with severe alcoholic
20% mortality reduction.
hepatitis to reduce short-term mortality (Grade A1). However, in
Our review published in 2017 (Pavlov 2017) included two new our present meta-analysis, we could not rule out a beneficial
trials (De 2014; Thursz 2015), compared with the previous review or harmful effect of glucocorticosteroids in people with severe
version published in a paper journal (Rambaldi 2008). The review alcoholic hepatitis.
by Pavlov 2017 excluded two of the trials from the Rambaldi 2008 as
they assessed glucocorticosteroids versus nutrition (Lesesne 1978;
AUTHORS' CONCLUSIONS
Cabré 2000). In addition, two trial reports turned out to be the same
Implications for practice
trial (Shumaker 1978; Galambos 1984), and thus, they are counted
as one trial (Pavlov 2017). We did not identify any new trials for the We are very uncertain about the effect estimate of no difference
update of this current review. between glucocorticosteroids and placebo or no intervention on
all-cause mortality and serious adverse events during treatment
because the risk of bias was high and the certainty of the evidence
Informed decisions.
was very low. Our confidence in the effect of glucocorticosteroids data, so that proper individual participant data meta-analyses of
on health-related quality of life is low. Due to inadequate the effects of glucocorticosteroids in subgroups can be conducted
reporting, we cannot exclude increases in adverse events. As (NTAWG 2015; Garattini 2016).
the confidence intervals, except for one-year all-cause mortality,
were wide, we cannot rule out significant benefits or harms of ACKNOWLEDGEMENTS
glucocorticosteroids.
Cochrane Review Group funding acknowledgement: the Danish
Implications for research State is the largest single funder of Cochrane Hepato-Biliary
through its investment in the Copenhagen Trial Unit, Centre for
As there could be some people with alcoholic hepatitis who Clinical Intervention Research, Copenhagen, Denmark. Disclaimer:
could benefit from glucocorticosteroids, it could be of use for the views and opinions expressed in this review are those of the
researchers to study further the effects of glucocorticosteroids authors and do not necessarily reflect those of the Danish State or
in randomised clinical trials on short-term all-cause mortality. the Copenhagen Trial Unit.
Additional evidence evaluating the effect on health-related quality
of life is also needed. Future trials ought to be designed Peer reviewers: Kurinchi S Gurusamy, UK; Michael Ronan Lucey,
according to the SPIRIT guidelines (www.spirit-statement.org/) USA.
and reported according to the CONSORT guidelines (www.consort- Contact editor: Dario Conte, Italy.
statement.org). Future trials ought to report individual participant Sign-off editor: Agostino Colli, Italy.

Informed decisions.
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Informed decisions.
CHARACTERISTICS OF STUDIES
Characteristics of included studies [ordered by study ID]
Blitzer 1977
Methods Prospective, double-blind randomised trial
Country: USA
Dates: 1971–1973
Intention-to-treat analysis: no
Sample size calculation: not reported
Participants Demographic characteristics
Age (mean): prednisolone group: 47.2 years; control group: 48.4 years
Sex: 100% men
Inclusion criteria and degree of severity
People with alcoholic hepatitis meeting the following criteria after ≥ 5 days in hospital: recent history of
heavy alcohol consumption (> 1 pint whiskey per day or alcoholic equivalent); hepatomegaly based on
physical examination (palpable > 5 cm below the costal margin) or liver scan or both; total serum biliru-
bin > 5 mg/100 mL; and ≥ 2 abnormalities of AST > 100 Reitman-Frankel units/mL, serum albumin con-
centration < 3 g/100 mL, or prothrombin time > 2 s greater than control value.
Liver biopsies: performed whenever possible, but were not required for admission to the study. 14
biopsies proved alcoholic hepatitis.
Neither positive PPD skin tests nor active tuberculosis excluded people from randomisation. No pos-
itive PPD skin tests, and 1 active tuberculosis continued to receive isoniazid and para-aminosalicylic
acid throughout the study. If serious life-threatening infection present, patients' entry into study was
postponed until it was eradicated. People with history of peptic ulcer, active peptic ulcer disease, or
gastrointestinal bleeding were included.
Severity of disease: not clearly described; however, participants probably had moderate-to-severe al-
coholic hepatitis, since they presented people with alcoholic hepatitis who met the described criteria.
Exclusion criteria
People treated with adrenocorticosteroid in the 6 months prior to admission or who showed evidence
of psychotic behaviour precluding their co-operation
Randomisation procedure
Random, sealed-envelope technique
Number of participants randomised: 33
Prednisolone group: n = 17
Control group: n = 16
Interventions Experimental group: oral prednisolone 10 mg 4 times a day for 14 days, 5 mg 4 times a day for 4 days,
2.5 mg 4 times a day for 4 days, and 2.5 mg twice a day for 4 days
Control group: placebo tablets; same schedule as prednisolone group
Additional interventions to the trial groups: participants encouraged to eat standard hospital 2600-
calorie diet and were offered supplements when caloric intake seemed inadequate. Low-protein, low-
sodium, and other special diets used as clinical situation dictated.

Informed decisions.
Blitzer 1977 (Continued)

Duration of treatment: 26 days
Follow-up after randomisation: 9 weeks
Outcomes Mortality
Liver biochemistry
Liver histology
Adverse events
Notes Quote: "There were no significant differences between them [participants] with respect to mean age,
sex, race, duration of hospitalization prior to entry into the study, frequency of histologically proved cir-
rhosis, or to the histologic severity of the alcoholic hepatitis."
Letter sent to authors in March 2000. No answer received. No further attempts were made as the trial
was conducted between 1971 and 1973.
1 participant received placebo treatment during trial. At the end of the therapy, due to lack of improve-
ment, the ward physician requested the code be broken. The participant received a 7-day course of
prednisolone. He died 17 days later; his death was included in the mortality data of the control group
on an intention-to-treat basis.
On the 26th day of treatment, 3 participants in control group and 1 in glucocorticosteroid group re-
ceived the alternative medication on a double-blind basis.
Quote: "Both prednisolone and placebo tablets were kindly supplied by the Upjohn Co., Kalamazoo,
Michigan."
Risk of bias
Bias Authors' judgement Support for judgement
Random sequence genera- Low risk Quote: "Patients were assigned by random, sealed-envelope technique to re-
tion (selection bias) ceive either placebo or steroid."
Allocation concealment Low risk Quote: "… sealed-envelope technique to receive either placebo or steroid."
(selection bias)
Blinding of participants Low risk Quote: "Only the pharmacist was aware of the type of therapy which any indi-
and personnel (perfor- vidual patient was receiving."
mance bias)
All outcomes
Blinding of outcome as- Unclear risk No information provided

sessment (detection bias)
All outcomes
Incomplete outcome data High risk Quote: "5 participants, who had each received less than 5 days of therapy,
(attrition bias) were subsequently excluded from analysis. Of these, three had left the hospi-
All outcomes tal against medical advice or withdrew from the study, and in two participants
experimental therapy had been stopped following gastrointestinal haemor-
rhage. One bled after 4 days of therapy from a gastric varix and the other from
an unknown site after three days of treatment. On breaking the code at the
end of the investigation, it was learned that all five participants had been in
the steroid group … Furthermore, the addition of two deaths among the five
excluded participants …"
3/17 (9%) people in prednisolone group and 0/16 (0%) people in control group
dropped out.

Informed decisions.
Blitzer 1977 (Continued)
Selective reporting (re- Low risk No protocol available. However, all-cause mortality, serious adverse events,
porting bias) and liver-related mortality were reported.
Other bias Low risk None suspected
Bories 1987
Methods Randomised controlled trial
Country: France
Dates: 1979–1982
Intention-to-treat analysis: yes
Sample size calculation: not reported.
Age (mean): prednisolone group: 41 years (range 26 to 68 years); control group: 49 years (range 30 to 70
years)
Sex: prednisolone group: 16 men and 8 women; control group: 11 men and 10 women
Not stated clearly, but mean level of bilirubin ≥ 147 (SD 30.78) mmol/L
Alcohol consumption: men: 155 (SD 46) g/day; women: 140 (SD 32) g/day
Exclusion criteria
48 excluded due to infections (n = 45), diabetes (n = 2), and tuberculosis (n = 1)
Random number table
Interventions Experimental group: oral prednisolone 40 mg/day
Control group: no intervention
Additional interventions to the trial groups: 1500 calories and protein 50 g/day. Encephalopathy
treated with lactulose and neomycin. In case of infection, participants received antibiotics.
Duration of treatment: 1 month
Duration of follow-up: 3 months after randomisation
Outcomes Mortality
Liver histology
Adverse events

Informed decisions.
Bories 1987 (Continued)
Notes Letter sent to authors in March 2000. No answer received
Risk of bias
Random sequence genera- Unclear risk Quote: "By random number table."
tion (selection bias)
Allocation concealment Unclear risk Not described

(selection bias)
Blinding of participants High risk Not blinded

and personnel (perfor-
mance bias)
All outcomes
Blinding of outcome as- Unclear risk No information

All outcomes
Incomplete outcome data Low risk No dropouts

(attrition bias)
All outcomes
Campra 1973
Methods Prospective randomised control trial
Country: USA
Date: 1971
Age (mean): prednisolone group 43.1 (SD 11.1) years; control group 42.7 (SD 8.1) years
Sex: prednisolone group: 40 (8%) men; control group: 35 (9%) men
Clinical diagnosis of severe acute alcoholic liver disease, absence of contraindication to corticosteroids
therapy, no history of liver disease.
Liver biopsy not required for inclusion since some participants had prothrombin time < 50% of normal
value.
Severity of disease: no clear definition
Exclusion criteria
Informed decisions.
Campra 1973 (Continued)

People with other known illness or illnesses
Previously prepared sealed envelopes
Number of participants randomised: 50 participants entered trial, but 5 subsequently withdrawn

when additional data favoured another diagnosis. 45 analysed (see 'Risk of bias' table).
Interventions Experimental group: oral prednisone 0.5 mg/kg bodyweight daily for 3 weeks; then 0.25 mg/kg body-
weight daily for 3 weeks
Additional interventions to the trial groups: vitamin supplements, folic acids; high calorie, high pro-
tein diet if tolerated. In people with encephalopathy, protein intake was reduced to 20 g or 40 g and
neomycin 500 mg 4 times daily was given. In case of bleeding, vomiting, and extreme anorexia, people
received 5% or 10% dextrose solutions.
Duration of treatment: 6 weeks
Duration of follow-up: hospital stay after randomisation: prednisolone group: 42–92 days, mean 47
days; control group: 43–95 days, mean 48 days
Outcomes Mortality
Liver biochemistry
Liver histology
Adverse events
Notes Letter sent to authors in March 2000. AG Redeker answered in January 2001 (see the 'Risk of bias' table)
Risk of bias
Random sequence genera- Low risk Quote: "… using previously prepared sealed envelopes, patients were random-
tion (selection bias) ly allocated to one of the two treatment groups."
Allocation concealment Low risk Information obtained through personal communication with the authors in
(selection bias) 2001 read: "they [envelopes] were never in the possession of the investigators,
but were kept by the department secretary who opened them upon request."
However, the publication reads: "using previously prepared sealed envelopes,

patients were randomly allocated to one of the two treatment groups."
Blinding of participants High risk Quote: "the trial was not double blind."
mance bias)
All outcomes
Blinding of outcome as- Unclear risk Quote: "… all statistical analyses and interpretation were done under supervi-
sessment (detection bias) sion of Dr. John Weiner of the Department of Biostatics, University of Southern
All outcomes California School of Medicine."

Informed decisions.
Campra 1973 (Continued)
Incomplete outcome data Low risk Quote: "50 patients entered the trial, but five were subsequently withdrawn
(attrition bias) when additional data favoured another diagnosis. In one case (group 2), jaun-
All outcomes dice proved to be caused by hepatitis B … the patient died … 2 of these pa-
tients were in group 2, one patient in group 1; all survived. The fifth patient
was removed from the trial when peptic ulcer was diagnosed after 15 days of
prednisolone therapy."
Total: prednisolone group: n = 22; control group: n = 28
Other bias Low risk Not suspected
Carithers 1989
Methods Randomised, multicentre, double-blind, placebo-controlled, clinical trial
Country: USA
Dates: 1979–1984
Sample size calculation: reported (calculated that 62 patients should be entered to have 95% chance of
detecting a difference in survival between the 2 groups).
Age (mean): methylprednisolone group: 43.1 (SD 2.0) years; control group: 44.4 (SD 1.7) years
Sex: methylprednisolone group: 20 (57%) men; control group: 21 (68%) men
History of long-standing alcoholism and clinical features of alcoholic hepatitis evaluated by 1 princi-
pal investigator within 3 days of admission; clinical evidence of spontaneous hepatic encephalopathy
(assessed using standard clinical criteria and present when correctable causes of encephalopathy had
been excluded) or a discriminant function value > 32 or both; negative hepatitis B surface antigen with-
in the first 3 days of hospitalisation; and no history of previous viral hepatitis
Exclusion criteria
Gastrointestinal haemorrhage requiring transfusions; diabetes requiring insulin administration; active

infection requiring treatment; clinical and laboratory evidence of acute pancreatitis; history of recent
head trauma; known prior heroin addiction; or pre-existing chronic renal disease with a serum creati-
nine > 175 mmol/L
Random code sequence generated and kept by an independent source (see 'Risk of bias' table)
Prednisolone group: n = 36 (2 refused, 1 was excluded from analysis); 33 analysed
Interventions Experimental group: methylprednisolone 32 mg/day (equivalent to 40 mg prednisolone). Single dose

of 8 tablets of 4 mg each morning for 28 days.

Informed decisions.
Carithers 1989 (Continued)

In participants unable to take oral medications, intravenous infusions of study drug administered dai-
ly (methylprednisolone sodium succinate (SoluMedrol) or identical placebo. After 4 weeks, 4 tablets ad-
ministered daily for 1 week followed by 2 tablets daily for 1 week; then therapy discontinued.
Control group: placebo; identical tablets
Additional treatment: participants offered 3000-caIorie diet. Protein (1–1.5 g/kg bodyweight) provid-
ed when no evidence of hepatic encephalopathy. Protein restricted to ≤ 20 g/day and lactulose therapy
instituted in participants with signs of hepatic encephalopathy. Ascites managed with sodium restric-
tion or by addition of spironolactone in participants who did not respond with diuresis within 5 days.
Fluid intake restricted in participants with hyponatraemia. B-compIex multivitamins and folic acid 1
mg given daily. Participants who developed tremulousness or delirium tremens received diazepam or
oxazepam.
Duration of treatment: 5 weeks; 28 days at 32 mg/day then 16 mg/day for 7 days
Duration of follow-up after randomisation: at discharge
Outcomes Mortality
Liver biochemistry
Adverse events
Notes Letter sent to authors in March 2000. No answer received
Risk of bias
Random sequence genera- Low risk Quote: "… Random sequences for drug or placebo were submitted to the Up-
tion (selection bias) john Company (Kalamazoo, Michigan), which provided methylprednisolone
(Medrol) in 4-mg tablets and identical placebo tablets as well as intravenous
preparations of methylprednisolone sodium succinate (SoluMedrol) and
placebo. A random code was prepared for each of the four participating insti-
tutions such that within each group of 10 patients, 5 would receive methyl-
prednisolone and 5 placebo. The random code sequence was kept by an inde-
pendent source."
Allocation concealment Low risk Quote: "the random code sequence was kept by an independent source."
(selection bias)
Blinding of participants Low risk Quote: "neither the principal investigators nor their associates were aware of
and personnel (perfor- which regimen patients received throughout the trial."
mance bias)
All outcomes
Blinding of outcome as- High risk Quote: "Data obtained at initial evaluation and follow-up were recorded on
sessment (detection bias) standardized data collection forms that were submitted to the statistical co-
All outcomes ordinating center at the end of each study … A study overview committee,
chaired by Dr. Hyman Zimmerman, reviewed the ongoing results of the study
on a yearly basis from reports generated by the statistical coordinating center,
which had access to the randomisation codes."
Incomplete outcome data Low risk 3%

(attrition bias)
All outcomes Quote: "One patient who received methylprednisolone was belatedly discov-
ered to have had neither encephalopathy nor elevation of discriminant func-
tion sufficient to meet the entry criteria and was excluded from analysis. Of
the remaining 66 patients, 64 remained in the hospital for the duration of the

Informed decisions.
Carithers 1989 (Continued)

study. Two methylprednisolone recipients refused to continue in the study.
The first patient signed out of the hospital after 10 days on the trial and was
alive at the end of the study. The second patient was discharged at his insis-
tence after 15 days on the trial and was given the study drug to take at home,
but he never returned for follow-up. His status at the end of the study was un-
known. He was the only patient lost to follow-up."
Prednisolone group: 2/36; control group: 0/31
De 2014
Methods Randomised controlled clinical trial
Country: Medical College and Hospital, Kolkata, India
Dates: January 2010 to August 2012
Study protocol approved by the institutional ethical committee.
Age (mean): pentoxifylline + prednisolone group: 42.73 (SD 0.43) years; pentoxifylline group: 41.33 (SD
7.81) years
Sex: 100% men
History of chronic alcohol intake > 50 g/day with clinical and biochemical features of severe alcoholic
hepatitis (MDF score ≥ 32 and AST:ALT > 2:1 with absolute value of AST < 500 IU/L and ALT < 200 IU/L
MELD score, GAHS, and Child-Pugh score calculated for all included participants.
Exclusion criteria
Other potential aetiology of liver injury (acute or chronic viral hepatitis, autoimmune liver disease, Wil-
son's disease) even in the background of chronic alcohol intake, positive for HIV antibodies or histo-
ry of abstinence from alcohol in the last month, infection, sepsis or spontaneous bacterial peritonitis,
acute pancreatitis, gastrointestinal bleeding, hepatorenal syndrome or any other severe associated
disease such as uncontrolled diabetes mellitus, systemic hypertension, heart failure, pulmonary dis-
ease or malignancy at the time of inclusion or in the previous 3 months.
Computer-generated randomisation table
Pentoxifylline + prednisolone group: n = 31 (1 voluntary dropped out)
Pentoxifylline group: n = 31 (1 vertigo and withdrew)
Interventions Experimental group: prednisolone (Wysolone, Wreath, Mumbai, India) 40 mg once daily for 4 weeks
+ pentoxifylline (Trental tablets, Sanofi Aventis, Mumbai, India) tablets 400 mg 3 times daily for first 4
weeks

Informed decisions.
De 2014 (Continued)
Control group: placebo tablet for 4 weeks + pentoxifylline 400 mg 3 times daily orally first 4 weeks
Duration of treatment: 11 weeks (12 weeks in group 1 (the control) and 11 weeks in group 2 (the ex-
perimental))
Quote: "After the initial 4 weeks, the study was opened and the patients allocated to different groups
were revealed. Patients in Group 1 (PTX [pentoxifylline]) who tolerated the drug well, continued to re-
ceive the medication at the same dose for the next 8 weeks and then stopped.
After 4 weeks of initial therapy, the dose of prednisolone in Group 2 was tapered by 5 mg/week over a
period of 7 weeks and then stopped and received PTX like Group 1 patients." (Thus, we could use only 3
months.)
Duration of follow-up: 12 months
Outcomes Mortality
Adverse events
Morbidity
Notes Quote: "One patient in Group 1 developed severe vertigo within 7 days after starting PTX, and one pa-
tient in Group 2 withdrew voluntarily from the study and hence they were excluded. A total of 60 pa-
tients, 30 in each group, were considered for the final analysis."
Letter sent to SK Mandal 12 December 2016. No reply received
Quote: "Prednisolone tablet (Wysolone, Wreath, Mumbai, India) and PTX (trental tablets, Sanofi Aventis,
Mumbai, India"
Risk of bias
Random sequence genera- Low risk Quote: "The recruited patients were then divided into 2 groups by a computer
tion (selection bias) generated randomization table."
Allocation concealment Unclear risk Unclear

(selection bias)
Blinding of participants Low risk Quote: "The investigator, who allocated the patients to the groups, adminis-
and personnel (perfor- tered the drugs and collected the clinical and laboratory data, as well as statis-
mance bias) ticians were all blinded regarding the nature of the pharmacotherapy."
All outcomes
Blinding of outcome as- Low risk Quote: "as well as statisticians were all blinded regarding the nature of the
sessment (detection bias) pharmacotherapy."
All outcomes
Incomplete outcome data Low risk 1.6%

(attrition bias)
All outcomes Quote: "One patient in Group 1 developed severe vertigo within 7 days after
starting PTX [pentoxifylline], and one patient in Group 2 withdrew voluntarily
from the study and hence they were excluded."

Informed decisions.
Depew 1980
Methods Randomised, double-blind, controlled clinical trial
Country: USA
Dates: 1977–1979
Study approved by the Human Experimentation Committee of the John Wesley County Hospital.
Sample size calculation: reported
Age (mean): prednisolone group: 49.8 (SD 2.1) years; control group: 48.2 (SD 2.3) years
Hepatic encephalopathy: prednisolone group: 100%; control group: 100%
Ascites: prednisolone group: 87%; control group: 92%
Alcohol abusers from lower socioeconomic strata with a clinical diagnosis of severe alcoholic hepatitis
manifested by hepatomegaly, leukocytosis, and a serum bilirubin > 5 mg/dL, spontaneous hepatic en-
cephalopathy occurring in absence of gastrointestinal haemorrhage, sedation, diuretic usage, or major
electrolyte disturbances.
Exclusion criteria
Quote: "Severe diabetes, active tuberculosis, and serious bacterial infection prevented participation in
the trial"
Liver biopsy was not required.
Unclear as not described (see 'Risk of bias' table)
Interventions Prednisolone group: prednisolone 40 mg daily orally
Control group: placebo
Additional treatment: supportive measures were attention to fluid and electrolyte balance, multi-
ple vitamin supplementation, and parenteral glucose administration when food intake was poor. En-
cephalopathy treated with catharsis, protein restriction, and oral neomycin
Duration of treatment: 28 days followed by tapered withdrawal over the ensuing 14 days
Duration of follow-up: 6 weeks
Outcomes Mortality
Liver biochemistry
Liver histology

Informed decisions.
Depew 1980 (Continued)

Adverse events
Notes Letter sent to authors in March 2000. No answer received. No further attempts were made as the trial
was conducted between 1977–1979.
Risk of bias
Random sequence genera- Unclear risk Not described.

Quote: "All patients fulfilling the criteria who gave informed consent were
randomised into two treatment protocols" and "… to avoid introducing bias
based on the presence of the hepatorenal syndrome, the randomisation pro-
cedure was stratified to distinguish those with a serum creatinine greater than
2.5 mg/dL."

(selection bias)
Blinding of participants Low risk Quote: "Neither the principal investigators nor the physicians attending the
and personnel (perfor- patients were aware of the identity of the coded drugs. Provision was made for
mance bias) breaking the code if serious complications developed which could be related
All outcomes to steroid therapy."
Blinding of outcome as- Unclear risk Not described

All outcomes
Incomplete outcome data Low risk No withdrawals and dropouts

(attrition bias)
All outcomes
Helman 1971
Country: USA
Age (mean): 47.8 years (range 30–67 years)
Sex: 12 men and 25 women
Diagnosis of alcoholic hepatitis confirmed by percutaneous needle biopsy. 70% of participants had
anaemia on admission attributed to folate deficiency, blood loss, alcoholism, and haemolysis

Informed decisions.
Helman 1971 (Continued)

Exclusion criteria
Biopsy could not be obtained within the first week of hospitalisation, gastrointestinal bleeding requir-
ing transfusion, or if PPD was positive.
Authors reported that participants were classified into three groups, according to clinical severity of
their disease. Quote: "Group I were severely ill – manifesting precoma or coma, group 2 were moder-
ately ill, but no evidence of encephalopathy, group 3 were asymptomatic ambulatory patients."
Random, double-blind technique. Determined by hospital pharmacist, without informing physicians,

nurses, or patients until completion of the study
Number of participants randomised: 37, divided in 3 groups according to severity of disease
Interventions Experimental group: prednisolone 40 mg daily
Control group: daily lactose placebo
Additional intervention: bed rest, high-protein (100 g) and high-calorie diet (3000 kcal) when tolerat-
ed and vitamin supplementation including folic acid. Sodium restriction instituted and all participants
with ascites and oedema were treated with diuretics.
Duration of treatment: 6 weeks: 4 weeks and 2-week period tapered
Duration of follow-up after randomisation: 4 months
Outcomes Mortality
Liver biochemistry
Liver histology
Adverse events
Notes Quote: "tablets 40 mg of prednisolone daily or lactose placebo (provided by Upjohn Co, Kalamazoo,
Mich)."
Letter sent to authors in March 2000. No answer received
Risk of bias
Random sequence genera- Unclear risk Not described.

Quote: "patients were selected by a random, double-blind technique …"
Allocation concealment Low risk Quote: "Drug treatment was randomly determined by the hospital pharma-
(selection bias) cist, without informing physicians, nurses, or patients until completion of the
study."
Blinding of participants Low risk Quote: "… The treatment code was broken during the study in only one case
and personnel (perfor- because of a medical emergency."
mance bias)
All outcomes

Informed decisions.
Helman 1971 (Continued)

All outcomes
Incomplete outcome data Low risk No withdrawals or dropouts

(attrition bias)
All outcomes
Selective reporting (re- High risk No protocol available. However, all-cause mortality and liver-related mortality
porting bias) were reported.
Other bias Low risk
Maddrey 1978
Methods Randomised, double-blind clinical trial with parallel-group design (3 groups)
Country: USA
Age (mean): prednisolone group: 40 (SD 8.5) years; control group: 42.3 (SD 11.1) years
History of long-standing and recent alcoholism referred to Liver Service (The Johns Hopkins Hospital).
Percutaneous liver biopsy performed unless precluded by coagulation abnormalities. Alcoholic hepati-
tis defined histologically as an inflammatory hepatic disease with cell swelling and hydropic change,
cell necrosis, and polymorphonuclear leukocytic infiltration.
Exclusion criteria
Active gastrointestinal haemorrhage, pancreatitis, history of peptic ulcer, active infection, presence
of hepatitis B infection, or history of previous viral hepatitis. MDF. People had wedged hepatic venous
pressure determination.
Random drug sequences
Participants randomised into 3 groups based on apparent severity of disease.
Group A (moderately ill), serum bilirubin > 3 mg/dL; hepatomegaly; and clotting factors adequate to al-
low liver biopsy
Group B (more severely ill), hyperbilirubinaemia and hepatomegaly as in A with additional presence of
ascites or hepatic encephalopathy (or both), but coagulation studies adequate for liver biopsy
Group C (severely ill), hyperbilirubinaemia and hepatomegaly as in A and B, with or without ascites or
hepatic encephalopathy (or both), but coagulation abnormalities precluded liver biopsy.

Informed decisions.
Maddrey 1978 (Continued)

Interventions Experimental group: prednisolone 40 mg/day orally; 8 × 5-mg tablets every morning
Control group: identical placebo tablets
Additional interventions to the trial groups: offered 3000 calorie diet. Protein 1–1.5 g/kg provided for
people with no evidence of hepatic encephalopathy. In people with encephalopathy, protein restric-
tion to ≤ 20 g/day and lactulose therapy. Ascites managed with sodium restriction alone or with the ad-
dition of spironolactone in people who did not respond with diuresis in 5 days. All participants initially
received thiamine 100 mg intramuscularly. B-complex multivitamins and folic acid given daily
Duration of treatment: 28–32 days
Follow-up: until discharge
Outcomes Early mortality
Complications of therapy
Liver function and haematological tests
Wedged hepatic venous pressure
Factors associated with a fatal outcome
Discriminant function analysis
Notes Study supported by Research Grant AA00201 from the National Institute of Alcohol Abuse and Alco-
holism of the National Institutes of Health, and by Grant RR-35 from the Clinical Research Centers Pro-
gram, United States Public Health Service.
Prednisolone and placebo tablets provided by the Division of Steroid Research, The Upjohn Company,
Kalamazoo, Mich. However, no further details were provided.
Letter sent to authors in March 2000. No answer received. No further attempts made.
Risk of bias
Random sequence genera- Low risk Quote: "Patients were randomised for treatment within three groups based on
tion (selection bias) apparent severity of disease. Random drug sequences were arranged within
each group."

(selection bias)
Blinding of participants Low risk Quote: "Prednisolone (5 mg) or identical placebo tablets were given in a single
and personnel (perfor- dose of 8 pills each morning for 28 to 32 days. (Prednisolone (5 mg) and identi-
mance bias) cal placebo tablets were provided by the Division of Steroid Research, The Up-
All outcomes john Company, Kalamazoo, Mich.). The investigators were not aware of which
regimen the patient was receiving until the completion of the study."

All outcomes
Incomplete outcome data Low risk 3.5% dropped out or were withdrawn.
(attrition bias)
All outcomes Quote: "Two additional patients were removed from the study after randomi-
sation. One patient who was randomised to the placebo group bled from oe-
sophageal varices before receiving the study drug. He subsequently stopped
Informed decisions.
Maddrey 1978 (Continued)

bleeding and survived. Another patient had an episode of upper gastrointesti-
nal haemorrhage presumably from oesophageal varices after receiving pred-
nisolone for 9 days and the drug was stopped."
Mendenhall 1977
Methods Prospective, randomised clinical trial (3 intervention groups)
Country: USA
Intention-to-treat analysis: not mentioned
Age: not reported
Sex: not reported; most probably men as they came from V.A. (Veteran Affairs) Medical Centers
History of daily ethanol ingestion > 100 g/day for ≥ 1 year; hepatomegaly (> 12 cm) and significant jaun-
dice (bilirubin > 5 mg %). Liver biopsy obtained in about 70% of participants to confirm diagnosis
Exclusion criteria
Not described
Not described, but mentioned that "regimens were chosen randomly and blinded so that neither physi-
cian nor patient was aware of the treatment modality."
Prednisolone group: n = 12 (all severe alcoholic hepatitis)
Control group: n = 17 (all severe alcoholic hepatitis)
Oxandrolone group: n = 17
Interventions Experimental group: prednisolone 60 mg/day × 5, then decreased over a 16-day period
Experimental group 2: oxandrolone (not included in the review)
Additional treatment: supportive care
Duration of follow-up: to discharge
Outcomes Mortality

Informed decisions.
Mendenhall 1977 (Continued)

Liver biochemistry
Notes Letter sent to study authors in 2006. No answer received.
Only published as an abstract
Risk of bias
Random sequence genera- Unclear risk Quote: "… regimens were chosen randomly."

(selection bias)
Blinding of participants Low risk Quote: "blinded so that neither physician nor patient was aware of the treat-
and personnel (perfor- ment modality."
mance bias)
All outcomes

All outcomes
Incomplete outcome data Low risk Quote: "one additional mortality withdrew from the study on the 8 day" (not
(attrition bias) mentioned from what group out of 50 participants
All outcomes
17 participants treated with oxandrolone
Selective reporting (re- High risk No protocol available. However, all-cause mortality was reported.
porting bias)
Mendenhall 1984
Methods Co-operative, multicentre, randomised clinical trial (3 intervention groups)
Country: USA
Dates: 1980–1983
Age (mean): prednisolone group: 51.5 (SD 8.2) years; control group 50.4 (SD 9.2) years
Sex: 100% men
Men hospitalised at 6 Veterans Administration Medical Centers in whom diagnosis of moderate or se-
vere alcoholic hepatitis was based on conventional clinical and laboratory changes of this disease. His-
tological confirmation not required, so severely ill people not excluded. Severity classified by degree of
jaundice (bilirubin) and coagulopathy (prothrombin time)

Informed decisions.

Exclusion criteria
Conditions that contradicted corticosteroid therapy: severe infections, active peptic ulcer disease,
or insulin-dependent diabetes mellitus, or if they had taken corticosteroids within the preceding 3
months; positive test for hepatitis B surface antigen; clinical or historical evidence of recent parenteral
drug abuse, intractable congestive heart failure, neoplasms that commonly metastasise to the liver, or
non-alcoholic liver diseases
Assignment made by Coordinating Center (Hines, Ill) was balanced within each hospital, and according
to disease severity
Number of participants randomised: 178 (prednisolone and placebo) + 85 (n = oxandrolone)
Prednisolone group: n = 90 (moderate 46, severe 44)
Control group: n = 88 (moderate 45, severe 43)
Oxandrolone group: 85
Interventions 132 participants with moderate disease and 131 with severe disease were randomly assigned to 1 of 3
treatments: prednisolone, oxandrolone, or placebo
Experimental group: prednisolone
Dose: 60 mg/day for 4 days; 40 mg/day for 4 days; 30 mg/day for 4 days; 20 mg/day for 4 days; 10 mg/
day for 7 days; 5 mg/day for 7 final days
Experimental group 2: oxandrolone (not included in the review)
When possible, participants were evaluated monthly at outpatient clinics. If alcoholic hepatitis re-
curred and required rehospitalisation, the person was reassigned to the same therapy for 30 days with
his permission.
Duration of follow-up after randomisation: 1 year (350 days for prednisolone group)
Outcomes Mortality
Liver complications
Liver biochemistry
Adverse events
Notes Matching placebos prepared by Upjohn Company and G.D. Searle and Company.
Risk of bias
Random sequence genera- Unclear risk Quote: "Treatment assignment was made by the Coordinating Center (Hines,
tion (selection bias) Ill.). The random assignment of treatments was balanced within each hospital,
as well as according to disease severity."
Allocation concealment Low risk Quote: "Treatment assignment were made by the Coordinating Center (Hines,
(selection bias) Ill)."

Informed decisions.
Blinding of participants Low risk Quote: "Medication was packed into unit dose kits at the Veterans Administra-
and personnel (perfor- tion Center Pharmacy(Albuquerque, N.M.). The patient, physician and the local
mance bias) hospital pharmacy had no knowledge of the specific medication in use."
All outcomes

All outcomes

(attrition bias)
All outcomes Quote: "Ten patients withdrew from the study before completing treatment (5
given placebo, 3 prednisolone). However, these patients were included in the
outcome assessment."
Quote: "324 days … 37 patients were lost to follow-up: 13 given placebo, 11

prednisolone."
Selective reporting (re- High risk No protocol available. However, all-cause mortality and liver-related mortality
porting bias) were reported.
Porter 1971
Methods Prospective, double-blind, controlled pilot trial
Country: USA
Age (mean): prednisolone group: 44.6 (SD 4.4) years; control group: 49.5 (SD 8.9) years; overall range
27–61 years)
History of recent heavy alcohol ingestion, serum bilirubin concentration ≥ 5 mg/100 mL, clinical and
laboratory deterioration over the first 5 hospital days, striking lack of improvement in the patient's clin-
ical and biochemical status over first 5 hospital days, or rapid marked deterioration in < 24 hours
For admission to the study all three absolute criteria were required. In addition, ≥ 2 major criteria or 1
major and ≥ 4 minor criteria had to be met. Major criteria: liver biopsy showing alcoholic hepatitis; he-
patic encephalopathy (including asterixis); persistent or progressive azotaemia not explained by anoth-
er process; and total bilirubin levels > 20 mg/100 mL. Minor criteria: fever not obviously secondary to
another process; white blood count > 12,000 not obviously secondary to another process; anorexia or
nausea or vomiting; palpable hepatomegaly; palpable splenomegaly; oesophageal varices; spider an-
giomas, oedema or ascites; palmar erythema; and prothrombin time prolonged ≥ 3 seconds over con-
trol.
The Australia antigen was absent from the serum of all 16 participants in whom it was sought. Before
the trial, a percutaneous needle biopsy of the liver was performed if the prothrombin time was not pro-
longed >4 seconds over control and there was no clinical bleeding tendency.
Informed decisions.
Porter 1971 (Continued)

Exclusion criteria
Active gastrointestinal bleeding, pancreatitis, radiological evidence of peptic-ulcer disease, active or

questionably active pulmonary tuberculosis, and potentially life-threatening bacterial infection
Number drawn from a pool
Number of participants randomised: 23 (20 analysed). 23 accepted to participate, but 3 died within
36 hours of start of therapy, and were excluded from analysis before code was broken, and did not re-
ceive adequate medication. Final series consisted of 20 participants
Interventions Prednisolone group: 6-methyl-prednisolone 50 mg (equivalent to prednisolone 50 mg, or hydrocor-

tisone 200 mg) in 3 divided doses, parenterally for the first 10 days. If clinical improvement occurred
over this interval and if nausea and vomiting were absent the drug was administered orally, and the
dose gradually tapered (decreased every second day by 4 mg for the 11th to the 18th days, by 2 mg for
the 19th to 30th days and every third day by 2 mg for the 31st to 45th days). If there was no clinical im-
provement within 10 days, the initial parenteral dose of 40 mg daily was continued until improvement
or death occurred.
Control group: placebo (lactose)
Additional treatment: early in study only participants with a positive intermediate strength PPD test
or a suspicious chest x-ray were given isoniazid; however, later in study, all participants received isoni-
azid. Received general supportive care required in hepatic decompensation. Special attention given to
fluid and electrolyte balance, prompt treatment of hepatic encephalopathy, and repeated evaluation
for infection. Most participants had daily estimation of the caloric and protein intake by a hospital di-
etitian. People unable to take oral nutrition received glucose ≥ 400 calories/day parenterally
Duration of treatment and of follow-up: 45 days after randomisation
Outcomes Mortality
Liver biochemistry
Liver histology
Adverse events
Notes Country: USA
Letter sent to study authors in March 2000. No answer received.
Quote: "Twenty-three patients were accepted for studying. However, three died within 36 hours of the
start of the therapy Quote: and were excluded from analysis before the code was broken because they
did not receive adequate medication."
Supported in part by a gastroenterology-research training grant (AM-05099) from the National Institute
of Arthritis and Metabolic Diseases (a portion of this work was conducted within the Clinical Research
Center of the University of Washington, with support by a grant MO1 FR-37 from the National Institutes
of Health.
Risk of bias
Random sequence genera- Low risk Quote: "the case was randomised into one of the two treatment groups. Both
tion (selection bias) the steroid (6-methyl prednisolone, or Medrol) and the placebo (lactose) were

Informed decisions.
Porter 1971 (Continued)

packaged and coded by number in both parenteral and oral forms (prepared
and supplied through the courtesy of the Upjohn Co, Kalamazoo, Mich) and
randomisation was achieved by a number drawn from a pool. Neither patients
nor physicians knew which form of treatment was used until the study had
been completed, when the code was broken."
Allocation concealment Low risk Quote: "the case was randomised into one of the two treatment groups. Both
(selection bias) the steroid (6-methyl prednisolone, or Medrol) and the placebo (lactose) were
packaged and coded by number in both parenteral and oral forms (prepared
and supplied through the courtesy of the Upjohn Co, Kalamazoo, Mich) …"
Blinding of participants Low risk Quote: "Neither patients nor physicians knew which form of treatment was
and personnel (perfor- used until the study had been completed, when the code was broken."
mance bias)
All outcomes
Blinding of outcome as- Low risk Quote: "At the conclusion of the study, all needle biopsy and post-mortem liver
sessment (detection bias) specimens were coded and read in blind review by the same observer."
All outcomes
Incomplete outcome data High risk 13%

(attrition bias)
All outcomes Quote: "Twenty three patients were accepted for study, three died within 36
hours of the start of therapy and were excluded from analysis before the code
was broken because they didn't receive adequate medication. The final series
thus consisted of 20 patients."
Ramond 1992
Methods Randomised, double-blind trial
Country: France
Dates: March 1987 to June 1990
Study approved by hospital ethics committees
124 people with alcohol dependence were admitted to 2 centres.
Age (mean): prednisolone group: 48.1 (SD 1.3) years; control group: 48.2 (SD 1.6) years
Sex: prednisolone group: 10 men; control group: 9 men
Computer-generated random code
Biopsy-confirmed alcoholic hepatitis (characterised by hyaline necrosis and infiltration of polymor-

phonuclear leukocytes) and spontaneous hepatic encephalopathy or a MDF > 32 (or both)

Informed decisions.
Ramond 1992 (Continued)

8 people died before inclusion in the trial.
Exclusion criteria
Gastrointestinal bleeding or bacterial infection excluded unless they could be effectively treated with-
in 48 hours; presence of hepatitis B surface antigen; presence of HIV antibodies; refusal of liver biopsy;
non-alcoholic hepatitis at histology
Number of participants randomised: 65 (4 excluded) (see 'Notes')
Prednisolone group: n = 33 (32 analysed)
Control group: n = 32 (29 analysed)
Interventions Prednisolone group: prednisolone (Solupred) 40 mg (prednisolone 40 mg equivalent methylpred-

nisolone 32 mg) given in single dose of 2 tablets each morning for 28 days. If participant was unable to
take oral medication, received intravenous infusions of prednisolone (Hydrocortancyl)
Control group: single dose of 2 tablets
Additional treatment: provided with 3000 kcal containing 1 g protein/kg. Participants with hepat-
ic encephalopathy received lactulose therapy. Ascites managed with sodium restriction or by adding
spironolactone to the treatment regimen. Received B complex multivitamins, folic acid, and antacids
daily
Duration of follow-up: 8 weeks
Outcomes Mortality
Liver biochemistry
Adverse events
Notes Letter sent to study authors in March 2000. No answer received.
Trial stopped at the first interim analysis after inclusion of 61 out of the planned 130 participants. Au-
thors used an alpha error < 0.025. This is too high a value to prevent early stopping at a random high.
Quote: "Drug therapy was interrupted by the attending physician if there was severe bacterial infection
or gastrointestinal bleeding, or if a corticosteroid-related complication was suspected … in patients
with such complications the remaining tablets of the study drug were replaced with placebo tablets
provided by the pharmacist (the only person who knew which regimen the patient had received first).
The principal investigator and their associates were not aware of randomisation procedure or of the
medication that the patients were receiving throughout the trial."
Quote: "65 patients were randomly assigned, but 4 were excluded – one patient assigned to receive
prednisolone was found to have anguilluliasis and her treatment was stopped one day after her inclu-
sion in the study. Three patients assigned to placebo were found not to have satisfied the inclusion cri-
teria. These 4 patients were alive at the end of treatment."
Prednisolone tablets and placebo were provided by Laboratoire Houdé (Paris).
Risk of bias
Random sequence genera- Low risk Quote: "a random code was prepared by computer for each participating cen-
tion (selection bias) tre … There was a different code prepared for men and women in each center,
so that within each group of six patients (male and female), three patients re-
ceived prednisolone and three received placebo."

Informed decisions.
Ramond 1992 (Continued)
Allocation concealment Low risk Quote: "a random code was prepared by computer for each participating cen-
(selection bias) tre. Random sequences of drug or placebo were prepared by the pharmacist at
each hospital."
Blinding of participants Low risk Quote: "a random code was prepared by computer for each participating cen-
and personnel (perfor- tre. Random sequences of drug or placebo were prepared by the pharmacist at
mance bias) each hospital."
All outcomes
Quote: "prednisolone (Solupred) in 20 mg tablets and identical placebo were
provided by the pharmacists at each hospital."
Blinding of outcome as- Unclear risk No information provided

All outcomes

(attrition bias)
All outcomes 1 woman left the hospital and then "she was re hospitalised 56 days after en-
rolment and left again the following day. She was the only patient lost to fol-
low up."
Richardet 1993
Methods Randomised clinical trial with a cross-over design
Country: France
Intention-to-treat analysis: not mentioned
No information
Non-infected people with histologically confirmed alcoholic hepatitis. All participants had severe he-
patic failure (prothrombin time < 50%, or bilirubin > 5.6 mg/dL, or encephalopathy)
Not mentioned
Glucocorticosteroid group: n = 12
Interventions Prednisolone group: prednisolone 40 mg daily
Control group: placebo 40 mg daily

Informed decisions.
Richardet 1993 (Continued)

Duration of treatment:
Prednisolone group: 1 week of treatment followed by 1 week of no treatment
Control group: 1 week of no treatment followed by 1 week of treatment
After that, both groups received glucocorticosteroids for 3 weeks.
Duration of follow-up: at discharge from hospital (3 months)
Outcomes Mortality
Liver biochemistry
Notes Letter sent to study authors in 2006. No answer received.
Only published as abstract
Risk of bias
Random sequence genera- Unclear risk No information

Allocation concealment Unclear risk No information

(selection bias)
Blinding of participants Unclear risk No information

mance bias)
All outcomes
Blinding of outcome as- Unclear risk No information

All outcomes
Incomplete outcome data Unclear risk No information

(attrition bias)
All outcomes
Selective reporting (re- Unclear risk No information

porting bias)
Other bias Unclear risk No information
Shumaker 1978
Methods Prospective, double-blind, randomised clinical trial
Country: USA
Intention-to-treat analysis: not mentioned, but presumably used
Sample size calculation: not reported.
Age (mean): prednisolone group/control group: 45,5/44,5

Informed decisions.
Shumaker 1978 (Continued)

Sex: prednisolone group: 25% men; control group: 44% men
History of recent heavy alcoholic ingestion, serum bilirubin > 5 mg %, hospitalisation for ≥ 5 days with-
out improvement in liver tests; or rapid deterioration of the clinical condition during a 24-hour period
while under observation. In addition, minimum of 2 major criteria or 1 major and 2 minor criteria to be
included. Major criteria: liver biopsy showing alcoholic hepatitis (with or without Mallory bodies), he-
patic encephalopathy, azotaemia unexplained by another process (blood urea nitrogen > 20 mg % or
creatinine > 1.5 mg %), hyperbilirubinaemia (> 20 mg %) and prothrombin time prolonged > 4 seconds
over control; and unresponsive to parenteral administration of vitamin K. Minor criteria included fever
not obviously secondary to another process, white blood count > 12,000, hepatomegaly (span > 14 cm),
splenomegaly, or liver stigmas (spider telangiectasias, palmar erythema, ascites, oedema, etc.)
Positive hepatitis B antigen did not exclude them from the study if a percutaneous liver biopsy con-
firmed alcoholic hepatitis.
Exclusion criteria
AST > 500 IU/L; active gastrointestinal bleeding; pancreatitis; x-ray evidence of peptic ulcer disease; ac-
tive or questionably active tuberculosis; active infection; or severe psychiatric disorder
Predetermined code provided by the drug manufacturer
Interventions Prednisolone group: 6-methylprednisolone 80 mg (equivalent to prednisolone 100 mg) for 4–7 days;
medication was then tapered on a flexible schedule with cessation of therapy planned for 4 weeks un-
less death or complications
Additional interventions to the trial groups: both groups received comparable supportive care re-
quired in hepatic decompensation. All participants with positive tuberculin tests were treated with iso-
niazid 300 mg daily and pyridoxine 50 mg daily.
Duration of treatment: 5 weeks; participants were placed on treatment for 4–7 days. Then the med-
ication was tapered on flexible schedule with cessation of therapy planned for 4 weeks unless death or
complication intervened.
Duration of follow-up: to hospital discharge
Outcomes Mortality
Liver histology
Adverse events
Notes Letter sent to study authors in March 2000. No answer received
Quote: "The patient was then randomised into a predetermined code provided by the drug manufac-
turer. (Upjohn Co., Kalamazoo, MI, prepared and supplied the medication and placebo."
Risk of bias

Informed decisions.
Shumaker 1978 (Continued)
Random sequence genera- Unclear risk Quote: "The patient was then randomised into a predetermined code provided
tion (selection bias) by the drug manufacturer. Immediately prior to randomisation, patients were
stratified into two categories based on the presence or abstinence of criteria
permitting liver biopsy" the purpose of this procedure was to provide compa-
rable case material for both steroid and placebo control groups.in the absence
of other contradictions, patients with prothrombin times less than four sec-
onds prolonged were placed in the "Biopsy feasible" group (n = 10) whether or
not they agreed to a biopsy. All other patients constituted the "Biopsy- Disal-
lowed" group (n = 17)."
Allocation concealment Low risk Quote: "The patient was then randomised into a predetermined code provided
(selection bias) by the drug manufacturer."
Blinding of participants Low risk Double-blind

mance bias) Quote: "80 mg of 6-methylprednisolone or equivalent number of placebo
All outcomes tablets (or parenteral therapy of the same dosage intravenously if gastroin-
testinal function precluded oral intake."
Blinding of outcome as- Low risk Quote: "Clinical evaluation was carried out by junior staff physicians blinded to
sessment (detection bias) treatment status of the patients."
All outcomes
Incomplete outcome data Low risk 3.7 %

(attrition bias)
All outcomes Quote: "a steroid treated patient voluntarily withdrew from the study after
eight days but was retained for statistical purposes."
Theodossi 1982
Country: UK
Age: not mentioned
Sex: prednisolone group: 19 men/8 women; control group: 12 men/16 women
Patients had to satisfy the following criteria: history of alcohol intake ≥ 80 g/day for ≥ 5 years; serum
bilirubin > 80 pmol/L (normal up to 20 µmol/L); serum AST level ≥ 2 × upper limit of normal (normal up
to 40 IU/L); prothrombin time prolonged by ≥ 9 seconds. Gastrointestinal bleeding, renal failure, and
sepsis did not invalidate entry.
Exclusion criteria

Informed decisions.
Theodossi 1982 (Continued)

Hepatoma and other diseases such as recent myocardial infarction, accompanying cerebrovascular ac-
cident including evidence of subdural haematoma, and active tuberculosis
Random sealed envelope
Number of participants: 60 (55 analysed). Referred from other hospitals because of the severity of
their illness. 5 excluded from the analyses because of doubts in initial diagnosis
Prednisolone group: n = 28 (analysed n = 27)
Control group: n = 32 (analysed n = 28)
Interventions Prednisolone group: intravenous methylprednisolone 1 g daily (equivalent to 1.25 g prednisolone) for
3 days
Additional treatment: participants who were too ill to take the standard hospital diet received a ≥
2000 calories as intravenous 20% glucose. Encephalopathy treated with protein restriction (maximum
of 20 g/day), lactulose (15–30 mL twice daily), and daily magnesium sulphate enemas
Duration of follow-up: little difference between groups in mean length of stay in hospital (pred-
nisolone group: 24.2 days; control group: 28.1 days)
Outcomes Mortality
Liver biochemistry
Adverse events
Notes Letter sent to study authors in March 2000. No answer received
Quote: "Of the 60 patients who satisfied the entry criteria, one in the treatment group and four in the
control group were excluded from the final analysis because subsequent findings in four cases cast
doubt on the initial diagnosis, and one patient was later found to have been given corticosteroids at
the referring hospital. Thus there were 27 patients in the treatment and 28 in the control group."
Risk of bias
Random sequence genera- Unclear risk Quote: "Patients … referred from other hospitals because of the severity of
tion (selection bias) their illness. Patients were allocated by random sealed envelope technique to
a control or treatment group …"
Allocation concealment Low risk Quote: "Patients were allocated by random sealed envelope technique to a
(selection bias) control or treatment group, …"
Blinding of participants High risk Not blinded

mance bias) Quote: "Patients were allocated by random sealed envelope technique to
All outcomes a control or treatment group, the latter receiving intravenous methylpred-
nisolone 1 g daily for three days."

All outcomes

Informed decisions.
Theodossi 1982 (Continued)
Incomplete outcome data High risk 8%

(attrition bias)
All outcomes Quote: "Of the 60 patients who satisfied the entry criteria, one in the treatment
group and four in the control group were excluded from the final analysis be-
cause subsequent findings in four cases cast doubt on the initial diagnosis,
and one patient was later found to have been given corticosteroids at the re-
ferring hospital. Thus, there were 27 patients in the treatment and 28 in the
control group."
Thursz 2015
Methods Multicentre, randomised trial with a 2 × 2 factorial design (09/MRE09/59).
Country: UK (65 hospitals)
Dates: January 2011 to February 2014
Age (mean): prednisolone plus placebo (n = 274) 49.3 ± 10.6); prednisolone plus pentoxifylline (n = 277)
48.6 ± 9.8; control group: placebo plus pentoxifylline (276) 47.9 ± 10.2; placebo plus placebo (276) 48.8 ±
10.3
Sex: glucocorticosteroid groups: 359 (65.6%) men; control groups: 326 (59.8%) men
Hepatic encephalopathy: glucocorticosteroid groups: 152 (28%); control groups: 143 (26%)
People abusing alcohol with a clinical diagnosis of severe alcoholic hepatitis manifested by he-
patomegaly, leukocytosis, serum bilirubin > 5 mg/dL, spontaneous hepatic encephalopathy; aged ≥ 18
years; clinical diagnosis of alcoholic hepatitis; mean alcohol consumption > 80 g/day for men and > 60
g/day for women; serum bilirubin > 80 μmol/L (4.7 mg/dL); discriminant function ≥ 32
Exclusion criteria
Jaundice for > 3 months; cessation of alcohol consumption for > 2 months before randomisation; pres-
ence of other causes of liver disease; serum AST > 500 IU/L or serum ALT > 300 IU/L; previous entry into
the study within the preceding 6 months
Web-based computer system
Number of participants randomised: 1103; data from 1053 were available for the primary end-point
analysis
Interventions Participants randomised to 1 of 4 groups: pentoxifylline-matched placebo + prednisolone-matched

placebo; pentoxifylline-matched placebo + prednisolone; pentoxifylline + prednisolone-matched
placebo; or pentoxifylline + prednisolone
Informed decisions.
Thursz 2015 (Continued)

Experimental groups: group 2 received prednisolone 40 mg daily + pentoxifylline-matched placebo (n
= 277); group 4 received prednisolone 40 mg daily + pentoxifylline 400 mg 3 times daily (n = 274)
Control groups: group 1 received pentoxifylline-matched placebo + prednisolone-matched placebo (n

= 276); group 3 received pentoxifylline 400 mg 3 times daily + prednisolone matched placebo (n = 276)
Additional interventions to the trial groups: standard supportive care and nutritional support. Clin-
ician made decision regarding other treatments, such as terlipressin for people with developing hepa-
torenal failure, acid suppression for prophylaxis against gastrointestinal haemorrhage, antibiotics, and
vitamin supplementation. People with renal failure (defined as creatinine level > 500 μmol/L (> 5.7 mg/
dL) or requirement for renal-replacement therapy), active gastrointestinal bleeding, or untreated sep-
sis, and people requiring inotropic support with adrenaline or noradrenaline, were excluded unless the
condition stabilised within the first 7 days after admission to hospital.
Duration of follow-up: 1 year
Outcomes Mortality
Adverse events
Quality of life (using the EQ-5D score registered to Eudra CT 2009-013897-42 and ISRCTN 88782125)
Notes European Quality of Life – 5 Dimension – 5 Level Scale (EQ-5D-5L): self-report, multiple choice ques-
tionnaire that provides a simple descriptive profile and a single index value for health status. Essen-
tially consists of 2 pages: the EQ-5D descriptive system (page 2) and the EQ VAS (page 3). The descrip-
tive system comprises: mobility, self-care, usual activities, pain/discomfort, and anxiety/depression.
Each dimension has 5 levels: no problems, slight problems, moderate problems, severe problems,
and extreme problems. The EQ VAS records the respondent's self-rated health on a vertical, VAS. The
EQ-5D-5L takes a few minutes to complete.
A summary index with a maximum score of 1 can be derived from these 5 dimensions by conversion
with a table of scores. The maximum score of 1 indicates the best health state, by contrast with the
scores of individual questions, where higher scores indicate more severe or frequent problems. In addi-
tion, there is a VAS to indicate the general health status with 100 indicating the best health status.
Study approved by the Multicenter Research Ethics Committee (reference number 09/MRE09/59), and
clinical trial authorisation received from the Medicines and Healthcare Products Regulatory Agency
(funded by the National Institute for Health Research Health Technology Assessment program; STOPAH
EudraCT number, 2009-013897-42, and Current Controlled Trials number, ISRCTN88782125.
Trial was conducted and reported according to the protocol, the Medicines for Human Use (Clinical
Trials) Regulations 2004, as amended in 2006, the European Union Clinical Trials Directive (Directive
2001/20/EC) guidelines, the principles of the International Conference on Harmonisation Good Clinical
Practice under the oversight of University Hospital Southampton NHS Foundation Trust, and the provi-
sions of the Declaration of Helsinki.
Letter sent to M Thursz 12 October 2016. No reply received yet
Risk of bias
Random sequence genera- Low risk Quote: "… A web-based computer system (Tenalea, Forms-Vision) was used
tion (selection bias) to enrol eligible patients and randomly assign them to study groups. The ran-
domization schedule was created with the use of Stata software, version 11
(StataCorp). Randomization was performed with a block size of four, with
stratification according to geographic area and risk category. The high-risk
category consisted of patients who had an occurrence of gastrointestinal
bleeding, renal impairment, or sepsis before randomisation. All other patients
were assigned to the intermediate-risk category."

Informed decisions.
Thursz 2015 (Continued)
Allocation concealment Low risk Quote: "The randomization schedule was created with the use of Stata soft-
(selection bias) ware, version 11 (StataCorp). Randomization was performed with a block size
of four, with stratification according to geographic area and risk category.
Treatment allocation was blinded to site staff and the patient by providing
each patient with a unique four-digit patient pack number."
Blinding of participants Low risk Double-blind

mance bias) Quote: "The treatment arm was also concealed to investigators and re-
All outcomes searchers. Only the study statisticians were unblinded and this was for analy-
sis purposes only."
Blinding of outcome as- Low risk Quote: "An independent data monitoring and ethics committee, whose mem-
sessment (detection bias) bers were aware of the group assignments, was convened to review the con-
All outcomes duct of the trial and to analyze primary end-point data, using prespecified
stopping guidelines, after the recruitment of 200, 400, and 800 patients, to
avoid continued recruitment in the event that a definitive result had been
achieved. Data collected by site investigative teams were submitted to the
clinical trials unit and analysed by study statisticians. The first author wrote
the first draft of the manuscript, with substantial contributions from the coau-
thors. All the authors vouch for the accuracy and completeness of the data and
analyses."
Incomplete outcome data Low risk Outcome data at the specific time points were reported.
(attrition bias)
All outcomes Quote: "At the time the trial was stopped, 33 patients who underwent random-
ization during the last 90 days of the trial could not be included in the 90-day
or 12-month analyses. In addition, there were 159 patients who underwent
randomization within 90 days to 12 months before the end of trial who could
not be included in 12-month analyses. The four groups were well matched
with regard to their baseline characteristics, including laboratory values (See
Table 1 in the published article). At 28 days, 16% of the patients had died, 1%
had been lost to follow-up, and 2% had withdrawn from the study. At 90 days,
29% of the patients (285 of 968 patients) had died, 5% had been lost to fol-
low-up, 3% had withdrawn, and 4% had not completed follow-up owing to
cessation of the study. At 1 year, 56% of the patients (421 of 747 patients) had
died or undergone liver transplantation (the latter were 3 patients), 8% had
been lost to follow-up, 4% had withdrawn, and 20% had not completed fol-
low-up owing to cessation of the study due to limitations on funding."
Quote: "Owing to limitations on funding, the trial was stopped after all en-
rolled patients had completed at least 28 days of follow-up."
Quote: "This project was funded by the National Institute for Health Research
(NIHR) Health Technology Assessment programme. The NIHR Clinical Research
Network provided research nurse support and the Imperial College Biomedical
Research Centre also provided funding."
Selective reporting (re- Low risk Protocol was available, and data on all protocol outcomes such as all-cause
porting bias) mortality, serious adverse events, liver-related mortality, and quality of life
were reported.
ALT: alanine aminotransferase; AST: aspartate aminotransferase; EQ-5D: European Quality of Life-5 dimensions; GAHS: Glasgow alcoholic
hepatitis score; MDF: Maddrey's Discriminant Function; MELD: model for end-stage liver disease; n: number of participants; PPD: purified
protein derivative; SD: standard deviation; VAS: visual analogue scale.

Informed decisions.
Characteristics of excluded studies [ordered by study ID]
Study Reason for exclusion
Alvarez 2004 Observational study (patient series). 13 participants with severe alcoholic hepatitis treated with
systemic glucocorticosteroids and total enteral nutrition.
Cabré 2000 Randomised trial of glucocorticosteroids versus nutrition in people with alcoholic hepatitis. Partici-
pants received oral or intravenous prednisolone or enteral nutrition (2000 kcal/day of a chemically
defined polymeric enteral diet enriched in branched-chain amino acids).
Christensen 1981 Quasi-randomised clinical study
Copenhagen 1969 Meta-analysis
Daures 1991 Meta-analysis
Dhanda 2016 Prospective single-centre cohort of people with severe alcoholic hepatitis treated with steroids; in-
cidence and significance of infection.
Galambos 1984 Reported in article through private contacts as part of Shumaker 1978.
Gill 1984 Trial randomised 10 people with severe alcoholic hepatitis to prednisolone, testosterone, and
amino acid supplement versus no intervention.
Goldis 2000 Observational study (patient series); the authors used a control group from the same centre.
Hozo 1996 Trial randomised people with alcoholic liver cirrhosis to glucocorticosteroids versus placebo.
Imperiale 1990 Meta-analysis
Lee 2016 Review
Lesesne 1978 Randomised trial of glucocorticosteroids versus nutrition in people with alcoholic hepatitis. Partic-
ipants received glucocorticosteroids plus permission to eat as they wanted or a maximum of 600
kcal/day as intravenous glucose, while the control group received caloric supplements of at least
1600 kcal/day.
Mal 1991 Abstract about influence of corticosteroids on the level of serum tumour necrosis factor concentra-
tions
Mathurin 2018 Trial randomised people with alcoholic hepatitis to receive selonsertib 18 mg versus placebo inflix-
imab versus placebo. All participants received prednisone 40 mg orally.
Mendenhall 1993 Chapter on alcoholic hepatitis in a book
Moreno 2014 Multicentral study with 2 groups of comparison of intensive enteral nutrition with complete nutri-
tion. Both groups received prednisolone.
Morris 2005 Observational study (patient series)
Naganuma 2014 Trial of granulocytapheresis and leukocytapheresis for the treatment of severe alcoholic hepatitis
Naveau 2004 Trial randomised people with alcoholic hepatitis to receive infliximab versus placebo. All partici-
pants received prednisone.
Phillips 2001 Trial randomised participants to antioxidants versus glucocorticosteroids.

Informed decisions.
Study Reason for exclusion
Poynard 1991 Meta-analysis on alcoholic hepatitis
Reynolds 1989 Narrative review on alcoholic hepatitis
Schlichting 1976 Quasi-randomised clinical study
Singal 2018 Review
Spahr 2002 Trial randomised people with alcoholic hepatitis to receive infliximab versus placebo. All partici-
pants received prednisone.
Stewart 2002 Trial stratified participants by gender and glucocorticosteroid use, and then randomised partici-
pants to receive antioxidants versus placebo.
Szabo 2018 Trial randomised people with alcoholic hepatitis to receive prednisolone 32 mg orally daily for 28
days versus a combination of anakinra + pentoxifylline + zinc orally
Tygstrup 1979 Meta-analysis
Characteristics of ongoing studies [ordered by study ID]
NCT03160651
Trial name or title Corticosteroids in severe alcoholic hepatitis patients with early spontaneous improvement
Methods Interventional (clinical trial). Double-blind randomised trial: Investigator, participants, and care
providers will be masked. Only statisticians and pharmacist will not be masked.
Participants Participants with alcoholic hepatitis: aged ≥ 18 years of either sex
Inclusion criteria: clinical syndrome of alcoholic hepatitis; recent jaundice or in recent aggravation
(< 3 months), serum bilirubin > 5 mg/dL, history of excess alcohol abuse (> 40 g/day); alcoholic he-
patitis confirmed by liver biopsy (histological criteria of alcoholic hepatitis defined according to
EASL clinical practice guidelines: steatosis, hepatocyte ballooning, and an inflammatory infiltrate
with PMNs); spontaneous liver function improvement, defined by a decrease in Maddrey Discrimi-
nant Function and serum bilirubin > 10% between admission and day 7 after admission
< 2 weeks since admission to hospital; Maddrey Discriminant Function ≥ 32; people must voluntar-
ily sign and date an informed consent form, approved by an Institutional Review Board/Indepen-
dent Ethics Committee prior to the initiation of any screening or study-specific procedures; be able
to understand and adhere to the study visit schedule and all other protocol requirements; people
with significant hepatic encephalopathy will not be excluded. In this case, the person should be ac-
companied by a legal representative who will decide participation in the clinical study and sign in-
formed consent form.
Exclusion criteria: other causes of liver disease including viral hepatitis (positive hepatitis B surface
antigen, HCV RNA positive), autoimmune hepatitis, biliary obstruction; other disease compromis-
ing 90-day survival; positive HIV serology; uncontrolled infection. All participants will be screened
for infection involving chest radiography, urinalysis, PMNs count in ascites (if ascites present). All
other sign or clinical suspicion of infection with or without antibiotherapy will be recorded as an in-
fection. Positive culture and initiation of antibiotics with clinical or radiological signs of infection,
as well as clinical suspicion, will be recorded as infection. People with evidence of sepsis will be
treated for a minimum of 2 days with appropriate antibiotics. Once the local principal investigator
considers that the sepsis is under control, the person may be rescreened and randomised. Uncon-
trolled gastrointestinal bleeding judged as controlled for ≥ 5 days; serum creatinine > 2.5 mg/dL,

Informed decisions.
NCT03160651 (Continued)
under renal replacement therapy or under terlipressin (or other vasoactive drugs); pentoxyphilline
therapy; pregnant or lactating women
Interventions Parallel assignment of methylprednisolone or placebo
Active comparator: methylprednisolone: methylprednisolone 32 mg/day for 28 days
Placebo comparator: matching placebo for 28 days
Outcomes Primary outcomes
Mortality at 90 days
Secondary outcome
Mortality at 28 days
Incidence of infections during the study period (90 days)
Starting date Estimated study start date: June 2017
Contact information Contact: Christophe Moreno, MD, PhD +32 2 5553714christophe.moreno@erasme.ulb.ac.be
Contact: Françoise Smits, Nurse +32 2 5554478francoise.smits@erasme.ulb.ac.be
Sponsors and collaborators: Erasme University Hospital
Principal investigator: Christophe Moreno, MD, PhD; Erasme University Hospital
Notes Estimated primary completion date: June 2020

Estimated study completion date: January 2021
EASL: European Association for the Study of the Liver; HCV: hepatitis C virus; MDF: Maddrey's Discriminant Function; PMN:
polymorphonuclear neutrophil.
DATA AND ANALYSES
Comparison 1. Glucocorticosteroids versus placebo/no intervention
Outcome or subgroup title No. of studies No. of partici- Statistical method Effect size
pants
1 All-cause mortality 15 Risk Ratio (M-H, Random, 95% Subtotals only

CI)
1.1 Up to 3 months' follow-up after 15 1861 Risk Ratio (M-H, Random, 95% 0.90 [0.70, 1.15]
randomisation CI)
1.2 At the end of treatment 14 1824 Risk Ratio (M-H, Random, 95% 0.87 [0.66, 1.15]
CI)
1.3 At 1 year after randomisation 3 1343 Risk Ratio (M-H, Random, 95% 1.03 [0.91, 1.17]
CI)
2 Health-related quality of life 1 Mean Difference (IV, Random, Totals not select-
95% CI) ed

Informed decisions.
pants
2.1 Up to 3 months 1 Mean Difference (IV, Random, 0.0 [0.0, 0.0]

95% CI)
2.2 Up to 1 year 1 Mean Difference (IV, Random, 0.0 [0.0, 0.0]

95% CI)
3 Serious adverse events during 15 1861 Risk Ratio (M-H, Random, 95% 1.05 [0.85, 1.29]
treatment CI)
4 Liver-related mortality: up to 3 15 1861 Risk Ratio (M-H, Random, 95% 0.89 [0.69, 1.14]
months' follow-up after randomisa- CI)
tion
5 Participants with any complica- 15 1861 Risk Ratio (M-H, Random, 95% 1.04 [0.86, 1.27]
tion up to 3 months' follow-up CI)
6 Participants with non-serious ad- 4 160 Risk Ratio (M-H, Fixed, 95% CI) 1.99 [0.72, 5.48]
verse events up to 3 months' fol-
low-up after randomisation
Analysis 1.1. Comparison 1 Glucocorticosteroids versus placebo/no intervention, Outcome 1 All-cause mortality.
Study or subgroup Glucocorti- Placebo/no Risk Ratio Weight Risk Ratio
costeroids intervention
n/N n/N M-H, Random, 95% CI M-H, Random, 95% CI
1.1.1 Up to 3 months' follow-up after randomisation
Blitzer 1977 8/17 5/16 5.55% 1.51[0.62,3.65]
Bories 1987 4/24 5/21 3.57% 0.7[0.22,2.27]
Campra 1973 7/22 10/28 6.51% 0.89[0.41,1.96]
Carithers 1989 2/36 11/31 2.58% 0.16[0.04,0.65]
De 2014 9/31 5/31 4.82% 1.8[0.68,4.76]
Depew 1980 8/15 7/13 7.71% 0.99[0.5,1.98]
Helman 1971 1/20 6/17 1.38% 0.14[0.02,1.06]
Maddrey 1978 3/25 6/32 3.09% 0.64[0.18,2.31]
Mendenhall 1977 4/12 2/17 2.29% 2.83[0.61,13.06]
Mendenhall 1984 34/90 35/88 13.63% 0.95[0.66,1.37]
Porter 1971 6/11 7/9 8.4% 0.7[0.37,1.33]
Ramond 1992 4/33 16/32 4.76% 0.24[0.09,0.65]
Shumaker 1978 6/12 7/15 6.57% 1.07[0.49,2.34]
Theodossi 1982 17/28 16/32 11.72% 1.21[0.77,1.92]
Thursz 2015 145/551 141/552 17.42% 1.03[0.84,1.26]
Subtotal (95% CI) 927 934 100% 0.9[0.7,1.15]
Total events: 258 (Glucocorticosteroids), 279 (Placebo/no intervention)
Heterogeneity: Tau2=0.08; Chi2=25.23, df=14(P=0.03); I2=44.52%
Test for overall effect: Z=0.85(P=0.4)
1.1.2 At the end of treatment

Blitzer 1977 4/17 2/16 2.75% 1.88[0.4,8.9]
Bories 1987 1/24 2/21 1.32% 0.44[0.04,4.49]
Campra 1973 7/22 10/28 7.7% 0.89[0.41,1.96]
Favours gluco 0.02 0.1 1 10 50 Favours plac/no inter

Informed decisions.

Carithers 1989 2/36 11/31 3.18% 0.16[0.04,0.65]
De 2014 9/31 5/31 5.8% 1.8[0.68,4.76]
Depew 1980 8/15 7/13 9% 0.99[0.5,1.98]
Maddrey 1978 3/25 6/32 3.79% 0.64[0.18,2.31]
Mendenhall 1977 4/12 2/17 2.83% 2.83[0.61,13.06]
Mendenhall 1984 18/90 16/88 10.34% 1.1[0.6,2.02]
Porter 1971 6/11 7/9 9.74% 0.7[0.37,1.33]
Ramond 1992 4/33 16/32 5.73% 0.24[0.09,0.65]
Shumaker 1978 6/12 7/15 7.77% 1.07[0.49,2.34]
Theodossi 1982 17/28 16/32 13.14% 1.21[0.77,1.92]
Thursz 2015 73/551 95/552 16.9% 0.77[0.58,1.02]
Subtotal (95% CI) 907 917 100% 0.87[0.66,1.15]
1.1.3 At 1 year after randomisation

De 2014 10/31 6/31 2.07% 1.67[0.69,4.02]
Mendenhall 1984 55/90 50/88 26.58% 1.08[0.84,1.38]
Thursz 2015 211/551 211/552 71.35% 1[0.86,1.16]
Subtotal (95% CI) 672 671 100% 1.03[0.91,1.17]
Heterogeneity: Tau2=0; Chi2=1.4, df=2(P=0.5); I2=0%
Analysis 1.2. Comparison 1 Glucocorticosteroids versus placebo/

no intervention, Outcome 2 Health-related quality of life.
Study or subgroup Glucocorticosteroids Placebo/no intervention Mean Difference Mean Difference
N Mean(SD) N Mean(SD) Random, 95% CI Random, 95% CI
1.2.1 Up to 3 months
Thursz 2015 191 0.6 (0.4) 186 0.6 (0.4) -0.04[-0.11,0.03]
1.2.2 Up to 1 year
Thursz 2015 88 0.6 (0.4) 82 0.6 (0.3) -0[-0.11,0.1]
Favours gluco -2 -1 0 1 2 Favours plac/no inter
Analysis 1.3. Comparison 1 Glucocorticosteroids versus placebo/

no intervention, Outcome 3 Serious adverse events during treatment.
Blitzer 1977 8/17 5/16 4.47% 1.51[0.62,3.65]
Bories 1987 4/24 2/21 1.58% 1.75[0.36,8.61]

Informed decisions.

Campra 1973 7/22 10/28 5.37% 0.89[0.41,1.96]
Carithers 1989 5/36 12/31 4.14% 0.36[0.14,0.91]
De 2014 9/31 6/31 4.3% 1.5[0.61,3.71]
Depew 1980 11/15 8/13 9.4% 1.19[0.7,2.02]
Helman 1971 9/20 6/17 5.19% 1.27[0.57,2.85]
Maddrey 1978 4/25 6/32 2.85% 0.85[0.27,2.7]
Mendenhall 1977 4/12 2/17 1.71% 2.83[0.61,13.06]
Mendenhall 1984 18/90 16/88 7.86% 1.1[0.6,2.02]
Porter 1971 6/11 7/9 7.25% 0.7[0.37,1.33]
Ramond 1992 4/33 16/32 3.76% 0.24[0.09,0.65]
Shumaker 1978 8/12 9/15 8.42% 1.11[0.63,1.97]
Theodossi 1982 20/28 16/32 12.12% 1.43[0.94,2.17]
Thursz 2015 244/551 217/552 21.58% 1.13[0.98,1.3]
Total (95% CI) 927 934 100% 1.05[0.85,1.29]

Analysis 1.4. Comparison 1 Glucocorticosteroids versus placebo/no intervention,

Outcome 4 Liver-related mortality: up to 3 months' follow-up after randomisation.
Helman 1971 1/20 6/17 1.42% 0.14[0.02,1.06]
Porter 1971 6/11 7/9 8.47% 0.7[0.37,1.33]
Campra 1973 7/22 10/28 6.61% 0.89[0.41,1.96]
Blitzer 1977 8/17 5/16 5.64% 1.51[0.62,3.65]
Mendenhall 1977 4/12 2/17 2.35% 2.83[0.61,13.06]
Shumaker 1978 6/12 7/15 6.66% 1.07[0.49,2.34]
Maddrey 1978 3/25 6/32 3.17% 0.64[0.18,2.31]
Depew 1980 8/15 7/13 7.79% 0.99[0.5,1.98]
Theodossi 1982 17/28 16/32 11.71% 1.21[0.77,1.92]
Mendenhall 1984 34/90 35/88 13.55% 0.95[0.66,1.37]
Bories 1987 3/24 5/21 3.08% 0.53[0.14,1.94]
Carithers 1989 2/36 11/31 2.64% 0.16[0.04,0.65]
Ramond 1992 4/33 16/32 4.85% 0.24[0.09,0.65]
Thursz 2015 145/551 141/552 17.14% 1.03[0.84,1.26]
De 2014 9/31 5/31 4.91% 1.8[0.68,4.76]
Total (95% CI) 927 934 100% 0.89[0.69,1.14]


Informed decisions.
Analysis 1.5. Comparison 1 Glucocorticosteroids versus placebo/no intervention,

Outcome 5 Participants with any complication up to 3 months' follow-up.
Blitzer 1977 10/17 5/16 4.38% 1.88[0.82,4.31]
Bories 1987 4/24 5/21 2.42% 0.7[0.22,2.27]
Campra 1973 8/22 10/28 5.18% 1.02[0.48,2.14]
Carithers 1989 5/36 12/31 3.66% 0.36[0.14,0.91]
De 2014 10/31 8/31 4.76% 1.25[0.57,2.74]
Depew 1980 13/15 8/13 9.37% 1.41[0.88,2.26]
Helman 1971 9/20 8/17 5.67% 0.96[0.48,1.92]
Maddrey 1978 7/25 7/32 3.78% 1.28[0.52,3.17]
Mendenhall 1977 4/12 2/17 1.51% 2.83[0.61,13.06]
Mendenhall 1984 34/90 35/88 11.96% 0.95[0.66,1.37]
Porter 1971 6/11 7/9 6.39% 0.7[0.37,1.33]
Ramond 1992 4/33 16/32 3.32% 0.24[0.09,0.65]
Shumaker 1978 8/12 9/15 7.42% 1.11[0.63,1.97]
Theodossi 1982 20/28 16/32 10.67% 1.43[0.94,2.17]
Thursz 2015 298/551 266/552 19.51% 1.12[1,1.26]
Total (95% CI) 927 934 100% 1.04[0.86,1.27]

Analysis 1.6. Comparison 1 Glucocorticosteroids versus placebo/no intervention, Outcome 6

Participants with non-serious adverse events up to 3 months' follow-up after randomisation.
n/N n/N M-H, Fixed, 95% CI M-H, Fixed, 95% CI
Blitzer 1977 2/17 0/16 9.87% 4.72[0.24,91.41]
De 2014 1/31 2/31 38.39% 0.5[0.05,5.23]
Depew 1980 2/15 0/13 10.24% 4.38[0.23,83.62]
Helman 1971 5/20 2/17 41.5% 2.13[0.47,9.59]
Total (95% CI) 83 77 100% 1.99[0.72,5.48]


Informed decisions.
Comparison 2. Subgroup analysis: all-cause mortality up to 3 months' follow-up after randomisation
pants
1 Bias risk 15 Risk Ratio (M-H, Random, 95% Subtotals only

CI)
1.1 Trials at low risk 1 1103 Risk Ratio (M-H, Random, 95% 1.03 [0.84, 1.26]
CI)
1.2 Trials at high risk 14 758 Risk Ratio (M-H, Random, 95% 0.86 [0.63, 1.17]
CI)
2 Trials without for-profit fund- 15 1861 Risk Ratio (M-H, Random, 95% 0.90 [0.70, 1.15]
ing compared to trials at risk of CI)
for-profit funding
2.1 Trials without for-profit fund- 1 1103 Risk Ratio (M-H, Random, 95% 1.03 [0.84, 1.26]
ing CI)
2.2 Trials at risk of for-profit 14 758 Risk Ratio (M-H, Random, 95% 0.86 [0.63, 1.17]
funding CI)
3 Severity of alcoholic hepatitis 15 Risk Ratio (M-H, Random, 95% Subtotals only
CI)
3.1 Mild alcoholic hepatitis 4 182 Risk Ratio (M-H, Random, 95% 1.02 [0.58, 1.80]
CI)
3.2 Severe alcoholic hepatitis 14 1679 Risk Ratio (M-H, Random, 95% 0.92 [0.73, 1.16]
CI)
4 Glucocorticosteroid (pred- 15 Risk Ratio (M-H, Random, 95% Subtotals only

nisolone) dose CI)
4.1 ≤ 40 mg 10 1547 Risk Ratio (M-H, Random, 95% 0.75 [0.50, 1.14]
CI)
4.2 > 40 mg 5 314 Risk Ratio (M-H, Random, 95% 1.02 [0.79, 1.30]
CI)
5 Alcoholic hepatitis without or 15 Risk Ratio (M-H, Random, 95% Subtotals only
with cirrhosis CI)
5.1 Without cirrhosis 3 123 Risk Ratio (M-H, Random, 95% 0.79 [0.18, 3.48]
CI)
5.2 With cirrhosis 12 1738 Risk Ratio (M-H, Random, 95% 0.92 [0.74, 1.16]
CI)
with hepatorenal syndrome CI)
6.1 With hepatorenal syndrome 8 1382 Risk Ratio (M-H, Random, 95% 1.00 [0.85, 1.17]
CI)
6.2 Without hepatorenal syn- 2 129 Risk Ratio (M-H, Random, 95% 0.56 [0.05, 6.49]
drome CI)

Informed decisions.
pants
with ascites CI)
7.1 With ascites 13 729 Risk Ratio (M-H, Random, 95% 0.82 [0.60, 1.12]
CI)
7.2 Unclear if they had ascites 1 29 Risk Ratio (M-H, Random, 95% 2.83 [0.61, 13.06]
CI)
Analysis 2.1. Comparison 2 Subgroup analysis: all-cause mortality

up to 3 months' follow-up after randomisation, Outcome 1 Bias risk.
2.1.1 Trials at low risk
Thursz 2015 145/551 141/552 100% 1.03[0.84,1.26]
Subtotal (95% CI) 551 552 100% 1.03[0.84,1.26]
Heterogeneity: Not applicable
2.1.2 Trials at high risk

Blitzer 1977 8/17 5/16 7.15% 1.51[0.62,3.65]
Bories 1987 4/24 5/21 4.93% 0.7[0.22,2.27]
Campra 1973 7/22 10/28 8.13% 0.89[0.41,1.96]
Carithers 1989 2/36 11/31 3.69% 0.16[0.04,0.65]
De 2014 9/31 5/31 6.37% 1.8[0.68,4.76]
Depew 1980 8/15 7/13 9.27% 0.99[0.5,1.98]
Helman 1971 1/20 6/17 2.07% 0.14[0.02,1.06]
Maddrey 1978 3/25 6/32 4.35% 0.64[0.18,2.31]
Mendenhall 1977 4/12 2/17 3.31% 2.83[0.61,13.06]
Mendenhall 1984 34/90 35/88 13.83% 0.95[0.66,1.37]
Porter 1971 6/11 7/9 9.88% 0.7[0.37,1.33]
Ramond 1992 4/33 16/32 6.3% 0.24[0.09,0.65]
Shumaker 1978 6/12 7/15 8.19% 1.07[0.49,2.34]
Theodossi 1982 17/28 16/32 12.52% 1.21[0.77,1.92]
Subtotal (95% CI) 376 382 100% 0.86[0.63,1.17]
Test for subgroup differences: Chi2=0.98, df=1 (P=0.32), I2=0%
Favours gluco 0.01 0.1 1 10 100 PFavours plac/no inter

Informed decisions.
Analysis 2.2. Comparison 2 Subgroup analysis: all-cause mortality up to 3 months' follow-up after
randomisation, Outcome 2 Trials without for-profit funding compared to trials at risk of for-profit funding.
2.2.1 Trials without for-profit funding
Thursz 2015 145/551 141/552 17.42% 1.03[0.84,1.26]
Subtotal (95% CI) 551 552 17.42% 1.03[0.84,1.26]
2.2.2 Trials at risk of for-profit funding

Blitzer 1977 8/17 5/16 5.55% 1.51[0.62,3.65]
Bories 1987 4/24 5/21 3.57% 0.7[0.22,2.27]
Campra 1973 7/22 10/28 6.51% 0.89[0.41,1.96]
Carithers 1989 2/36 11/31 2.58% 0.16[0.04,0.65]
De 2014 9/31 5/31 4.82% 1.8[0.68,4.76]
Depew 1980 8/15 7/13 7.71% 0.99[0.5,1.98]
Helman 1971 1/20 6/17 1.38% 0.14[0.02,1.06]
Maddrey 1978 3/25 6/32 3.09% 0.64[0.18,2.31]
Mendenhall 1977 4/12 2/17 2.29% 2.83[0.61,13.06]
Mendenhall 1984 34/90 35/88 13.63% 0.95[0.66,1.37]
Porter 1971 6/11 7/9 8.4% 0.7[0.37,1.33]
Ramond 1992 4/33 16/32 4.76% 0.24[0.09,0.65]
Shumaker 1978 6/12 7/15 6.57% 1.07[0.49,2.34]
Theodossi 1982 17/28 16/32 11.72% 1.21[0.77,1.92]
Subtotal (95% CI) 376 382 82.58% 0.86[0.63,1.17]
Total (95% CI) 927 934 100% 0.9[0.7,1.15]

Analysis 2.3. Comparison 2 Subgroup analysis: all-cause mortality up to 3

months' follow-up after randomisation, Outcome 3 Severity of alcoholic hepatitis.
2.3.1 Mild alcoholic hepatitis
Bories 1987 4/24 5/21 23.5% 0.7[0.22,2.27]
Helman 1971 0/11 0/11 Not estimable
Maddrey 1978 0/11 0/13 Not estimable
Mendenhall 1984 14/46 12/45 76.5% 1.14[0.59,2.19]
Subtotal (95% CI) 92 90 100% 1.02[0.58,1.8]
Favours glucoc 0.01 0.1 1 10 100 Favours plac/no inter

Informed decisions.

2.3.2 Severe alcoholic hepatitis

Blitzer 1977 8/17 5/16 5.55% 1.51[0.62,3.65]
Campra 1973 5/22 10/28 5.24% 0.64[0.25,1.59]
Carithers 1989 2/36 11/31 2.47% 0.16[0.04,0.65]
De 2014 9/31 5/31 4.77% 1.8[0.68,4.76]
Depew 1980 8/15 7/13 7.94% 0.99[0.5,1.98]
Helman 1971 1/9 6/6 2.29% 0.16[0.04,0.72]
Maddrey 1978 3/14 6/19 3.35% 0.68[0.2,2.26]
Mendenhall 1977 4/12 2/17 2.19% 2.83[0.61,13.06]
Mendenhall 1984 20/44 23/43 13.63% 0.85[0.55,1.3]
Porter 1971 6/11 7/9 8.74% 0.7[0.37,1.33]
Ramond 1992 4/33 6/32 3.52% 0.65[0.2,2.08]
Shumaker 1978 6/12 7/15 6.66% 1.07[0.49,2.34]
Theodossi 1982 17/28 16/32 12.81% 1.21[0.77,1.92]
Thursz 2015 145/551 141/552 20.85% 1.03[0.84,1.26]
Subtotal (95% CI) 835 844 100% 0.92[0.73,1.16]
Favours glucoc 0.01 0.1 1 10 100 Favours plac/no inter
Analysis 2.4. Comparison 2 Subgroup analysis: all-cause mortality up to 3 months'

follow-up after randomisation, Outcome 4 Glucocorticosteroid (prednisolone) dose.
2.4.1 ≤ 40 mg
Blitzer 1977 8/17 5/16 10.76% 1.51[0.62,3.65]
Bories 1987 4/24 5/21 7.79% 0.7[0.22,2.27]
Campra 1973 7/22 10/28 11.98% 0.89[0.41,1.96]
Carithers 1989 2/36 11/31 6% 0.16[0.04,0.65]
De 2014 9/31 5/31 9.75% 1.8[0.68,4.76]
Depew 1980 8/15 7/13 13.33% 0.99[0.5,1.98]
Helman 1971 1/20 6/17 3.5% 0.14[0.02,1.06]
Maddrey 1978 3/25 6/32 6.96% 0.64[0.18,2.31]
Ramond 1992 4/33 16/32 9.65% 0.24[0.09,0.65]
Thursz 2015 145/551 141/552 20.27% 1.03[0.84,1.26]
Subtotal (95% CI) 774 773 100% 0.75[0.5,1.14]
2.4.2 > 40 mg

Informed decisions.

Mendenhall 1977 4/12 2/17 2.58% 2.83[0.61,13.06]
Mendenhall 1984 34/90 35/88 44.16% 0.95[0.66,1.37]
Porter 1971 6/11 7/9 14.59% 0.7[0.37,1.33]
Shumaker 1978 6/12 7/15 9.83% 1.07[0.49,2.34]
Theodossi 1982 17/28 16/32 28.85% 1.21[0.77,1.92]
Subtotal (95% CI) 153 161 100% 1.02[0.79,1.3]
Test for subgroup differences: Chi2=1.48, df=1 (P=0.22), I2=32.52%

follow-up after randomisation, Outcome 5 Alcoholic hepatitis without or with cirrhosis.
2.5.1 Without cirrhosis
Carithers 1989 2/36 11/31 31.14% 0.16[0.04,0.65]
Mendenhall 1977 4/12 2/17 29.89% 2.83[0.61,13.06]
Shumaker 1978 6/12 7/15 38.97% 1.07[0.49,2.34]
Subtotal (95% CI) 60 63 100% 0.79[0.18,3.48]
2.5.2 With cirrhosis

Blitzer 1977 8/17 5/16 5.43% 1.51[0.62,3.65]
Bories 1987 4/24 5/21 3.33% 0.7[0.22,2.27]
Campra 1973 7/22 10/28 6.53% 0.89[0.41,1.96]
De 2014 9/31 5/31 4.63% 1.8[0.68,4.76]
Depew 1980 8/15 7/13 7.98% 0.99[0.5,1.98]
Helman 1971 1/20 6/17 1.23% 0.14[0.02,1.06]
Maddrey 1978 3/25 6/32 2.85% 0.64[0.18,2.31]
Mendenhall 1984 34/90 35/88 16.74% 0.95[0.66,1.37]
Porter 1971 6/11 7/9 8.85% 0.7[0.37,1.33]
Ramond 1992 4/33 16/32 4.56% 0.24[0.09,0.65]
Theodossi 1982 17/28 16/32 13.57% 1.21[0.77,1.92]
Thursz 2015 145/551 141/552 24.3% 1.03[0.84,1.26]
Subtotal (95% CI) 867 871 100% 0.92[0.74,1.16]

Informed decisions.
Analysis 2.6. Comparison 2 Subgroup analysis: all-cause mortality up to 3 months' follow-

up after randomisation, Outcome 6 Alcoholic hepatitis without or with hepatorenal syndrome.
2.6.1 With hepatorenal syndrome
Campra 1973 7/22 10/28 4.18% 0.89[0.41,1.96]
Depew 1980 8/15 7/13 5.44% 0.99[0.5,1.98]
Helman 1971 1/20 6/17 0.64% 0.14[0.02,1.06]
Maddrey 1978 3/25 6/32 1.58% 0.64[0.18,2.31]
Porter 1971 6/11 7/9 6.29% 0.7[0.37,1.33]
Shumaker 1978 6/12 7/15 4.24% 1.07[0.49,2.34]
Theodossi 1982 17/28 16/32 12.43% 1.21[0.77,1.92]
Thursz 2015 145/551 141/552 65.21% 1.03[0.84,1.26]
Subtotal (95% CI) 684 698 100% 1[0.85,1.17]
2.6.2 Without hepatorenal syndrome

Carithers 1989 2/36 11/31 47.73% 0.16[0.04,0.65]
De 2014 9/31 5/31 52.27% 1.8[0.68,4.76]
Subtotal (95% CI) 67 62 100% 0.56[0.05,6.49]
Heterogeneity: Tau2=2.74; Chi2=8.05, df=1(P=0); I2=87.57%

follow-up after randomisation, Outcome 7 Alcoholic hepatitis without or with ascites.
2.7.1 With ascites
Blitzer 1977 8/17 5/16 7.36% 1.51[0.62,3.65]
Bories 1987 4/24 5/21 5.04% 0.7[0.22,2.27]
Campra 1973 7/22 10/28 8.39% 0.89[0.41,1.96]
Carithers 1989 2/36 11/31 3.75% 0.16[0.04,0.65]
De 2014 9/31 5/31 6.53% 1.8[0.68,4.76]
Depew 1980 8/15 7/13 9.59% 0.99[0.5,1.98]
Helman 1971 1/20 6/17 2.1% 0.14[0.02,1.06]
Maddrey 1978 3/25 6/32 4.43% 0.64[0.18,2.31]
Mendenhall 1984 34/90 35/88 14.54% 0.95[0.66,1.37]
Porter 1971 6/11 7/9 10.25% 0.7[0.37,1.33]
Ramond 1992 4/33 16/32 6.46% 0.24[0.09,0.65]
Shumaker 1978 6/12 7/15 8.45% 1.07[0.49,2.34]
Theodossi 1982 17/28 16/32 13.1% 1.21[0.77,1.92]
Subtotal (95% CI) 364 365 100% 0.82[0.6,1.12]

Informed decisions.

2.7.2 Unclear if they had ascites

Mendenhall 1977 4/12 2/17 100% 2.83[0.61,13.06]
Subtotal (95% CI) 12 17 100% 2.83[0.61,13.06]
Test for subgroup differences: Chi2=2.41, df=1 (P=0.12), I2=58.57%
Comparison 3. Sensitivity analysis: all-cause mortality
pants
1 Best-worst scenario all-cause mortality up to 15 1861 Risk Ratio (M-H, Ran- 0.82 [0.64, 1.05]
3 months' follow-up after randomisation dom, 95% CI)
2 Worst-best scenario analysis: all-cause mor- 15 1861 Risk Ratio (M-H, 1.21 [1.06, 1.37]
tality up to 3 months' follow-up after randomi- Fixed, 95% CI)
sation
Analysis 3.1. Comparison 3 Sensitivity analysis: all-cause mortality, Outcome 1 Best-

worst scenario all-cause mortality up to 3 months' follow-up after randomisation.
Blitzer 1977 8/17 5/16 5.45% 1.51[0.62,3.65]
Bories 1987 4/24 5/21 3.51% 0.7[0.22,2.27]
Campra 1973 7/22 10/28 6.39% 0.89[0.41,1.96]
Carithers 1989 2/36 11/31 2.53% 0.16[0.04,0.65]
De 2014 9/31 6/31 5.27% 1.5[0.61,3.71]
Depew 1980 8/15 7/13 7.56% 0.99[0.5,1.98]
Helman 1971 1/20 6/17 1.36% 0.14[0.02,1.06]
Maddrey 1978 3/25 6/32 3.04% 0.64[0.18,2.31]
Mendenhall 1977 4/12 2/17 2.25% 2.83[0.61,13.06]
Mendenhall 1984 34/90 35/88 13.36% 0.95[0.66,1.37]
Porter 1971 6/11 7/9 8.24% 0.7[0.37,1.33]
Ramond 1992 4/33 16/32 4.67% 0.24[0.09,0.65]
Shumaker 1978 6/12 7/15 6.45% 1.07[0.49,2.34]
Theodossi 1982 17/28 19/32 12.4% 1.02[0.68,1.55]
Thursz 2015 145/551 209/552 17.52% 0.7[0.58,0.83]
Total (95% CI) 927 934 100% 0.82[0.64,1.05]
Favours gluco 0.02 0.1 1 10 50 Favours plac/no interv

Informed decisions.

Favours gluco 0.02 0.1 1 10 50 Favours plac/no interv
Analysis 3.2. Comparison 3 Sensitivity analysis: all-cause mortality, Outcome 2 Worst-

best scenario analysis: all-cause mortality up to 3 months' follow-up after randomisation.
Helman 1971 1/20 6/17 2.33% 0.14[0.02,1.06]
Porter 1971 6/11 7/9 2.77% 0.7[0.37,1.33]
Campra 1973 8/22 10/28 3.16% 1.02[0.48,2.14]
Mendenhall 1977 4/12 2/17 0.59% 2.83[0.61,13.06]
Blitzer 1977 11/17 5/16 1.85% 2.07[0.92,4.64]
Shumaker 1978 6/12 7/15 2.24% 1.07[0.49,2.34]
Maddrey 1978 3/25 6/32 1.89% 0.64[0.18,2.31]
Depew 1980 8/15 7/13 2.69% 0.99[0.5,1.98]
Theodossi 1982 18/28 16/32 5.36% 1.29[0.83,2]
Mendenhall 1984 34/90 35/88 12.71% 0.95[0.66,1.37]
Bories 1987 4/24 5/21 1.92% 0.7[0.22,2.27]
Carithers 1989 4/36 11/31 4.25% 0.31[0.11,0.88]
Ramond 1992 5/33 16/32 5.84% 0.3[0.13,0.73]
Thursz 2015 212/551 141/552 50.6% 1.51[1.26,1.8]
De 2014 10/31 5/31 1.8% 2[0.77,5.18]
Total (95% CI) 927 934 100% 1.21[1.06,1.37]

Heterogeneity: Tau2=0; Chi2=37.13, df=14(P=0); I2=62.3%
Test for overall effect: Z=2.83(P=0)
Comparison 4. Sensitivity analysis: serious adverse events
pants
1 Best-worse scenario of serious adverse 15 1861 Risk Ratio (M-H, Ran- 1.00 [0.83, 1.21]
events during treatment dom, 95% CI)
2 Worst-best scenario of serious adverse 15 1861 Risk Ratio (M-H, Fixed, 1.18 [1.05, 1.31]
events during treatment 95% CI)

Informed decisions.
Analysis 4.1. Comparison 4 Sensitivity analysis: serious adverse events,

Outcome 1 Best-worse scenario of serious adverse events during treatment.
Blitzer 1977 8/17 5/16 3.93% 1.51[0.62,3.65]
Bories 1987 4/24 2/21 1.33% 1.75[0.36,8.61]
Campra 1973 7/22 10/28 4.78% 0.89[0.41,1.96]
Carithers 1989 5/36 12/31 3.62% 0.36[0.14,0.91]
De 2014 9/31 7/31 4.18% 1.29[0.55,3.02]
Depew 1980 11/15 8/13 8.92% 1.19[0.7,2.02]
Helman 1971 9/20 6/17 4.61% 1.27[0.57,2.85]
Maddrey 1978 4/25 6/32 2.45% 0.85[0.27,2.7]
Mendenhall 1977 4/12 2/17 1.44% 2.83[0.61,13.06]
Mendenhall 1984 18/90 16/88 7.28% 1.1[0.6,2.02]
Porter 1971 6/11 7/9 6.65% 0.7[0.37,1.33]
Ramond 1992 4/33 16/32 3.27% 0.24[0.09,0.65]
Shumaker 1978 8/12 9/15 7.87% 1.11[0.63,1.97]
Theodossi 1982 20/28 19/32 13.82% 1.2[0.83,1.74]
Thursz 2015 244/551 242/552 25.86% 1.01[0.88,1.15]
Total (95% CI) 927 934 100% 1[0.83,1.21]

Analysis 4.2. Comparison 4 Sensitivity analysis: serious adverse events,

Outcome 2 Worst-best scenario of serious adverse events during treatment.
Blitzer 1977 11/17 5/16 1.53% 2.07[0.92,4.64]
Bories 1987 4/24 2/21 0.63% 1.75[0.36,8.61]
Campra 1973 8/22 10/28 2.61% 1.02[0.48,2.14]
Carithers 1989 7/36 12/31 3.83% 0.5[0.23,1.12]
De 2014 10/31 6/31 1.78% 1.67[0.69,4.02]
Depew 1980 11/15 8/13 2.54% 1.19[0.7,2.02]
Helman 1971 9/20 6/17 1.93% 1.27[0.57,2.85]
Maddrey 1978 4/25 6/32 1.56% 0.85[0.27,2.7]
Mendenhall 1977 4/12 2/17 0.49% 2.83[0.61,13.06]
Mendenhall 1984 18/90 16/88 4.8% 1.1[0.6,2.02]
Porter 1971 6/11 7/9 2.29% 0.7[0.37,1.33]
Ramond 1992 5/33 16/32 4.82% 0.3[0.13,0.73]
Shumaker 1978 8/12 9/15 2.38% 1.11[0.63,1.97]
Theodossi 1982 21/28 16/32 4.43% 1.5[1,2.25]
Thursz 2015 269/551 217/552 64.37% 1.24[1.09,1.42]
Total (95% CI) 927 934 100% 1.18[1.05,1.31]


Informed decisions.

Heterogeneity: Tau2=0; Chi2=22.56, df=14(P=0.07); I2=37.95%
Test for overall effect: Z=2.88(P=0)

ADDITIONAL TABLES
Table 1. Number of participants with most often occurring serious adverse events during treatment
Trial Gastrointestinal haemor- Hepatorenal syndrome Septicaemia Hepatocellular carcinoma
Library
Cochrane
rhage (with or without hepatic
failure)
Prednisolone Control Prednisolone Control Pred- Control Pred- Control

nisolone nisolone
Better health.
Informed decisions.
Trusted evidence.
Helman 1971 — — — 3 — — — —
Porter 1971 4 2 — — — — — —
Campra 1973 3 5 — 4 — — — —
Blitzer 1977 3 2 — 2 2 fungal — — 1
Mendenhall 1977 Not reported — — — — — — —
Maddrey 1978 1 1 3 6 — — — —
Shumaker 1978 3 3 — — 2 — —
Depew 1980 2 1 — — 2 1 — —
Theodossi 1982 11 6 — — 7 6 — —
Bories 1987 3 3 — 2 — — — —
Carithers 1989 2 4 — — 1 — — —
Mendenhall 1984 — — — — — — — 2

Ramond 1992 1 2 — — 1 1 — —
De 2014 2 3 3 — 3 1 — —
Richardet 1993 is missing from the table as no data were provided for quantitative analysis.
For Thursz 2015, see Table 2.
84
Informed decisions.
Table 2. Most often occurring serious adverse events in Thursz trial: number of events
Type of adverse event Prednisolone group Control group
Gastrointestinal haemorrhage plus 40 28
variceal bleeding
Infections 74 43
– lung 38 17
– sepsis 14 14
APPENDICES
Appendix 1. Search strategies
Database Search performed Search strategy
Cochrane Hepato-Bil- January 2019 (glucocortico* or steroid* or dexamethasone or prednis* or hydrocortisone or

iary Controlled Trials corticosteroid* or cortiso* or budesonide* or beclomethasone*) AND (alcohol*
Register and (liver or hepati*))
Cochrane Central Reg- Issue 1, 2019 #1 MeSH descriptor: [Adrenal Cortex Hormones] explode all trees
ister of Controlled Tri-
als (CENTRAL) in the #2 (glucocortico* or steroid* or dexamethasone or prednis* or hydrocortisone
Cochrane Library or corticosteroid* or cortiso* or budesonide* or beclomethasone*)
#3 #1 or #2
#4 MeSH descriptor: [Hepatitis, Alcoholic] explode all trees
#5 (alcohol* and (liver or hepati*))
#6 #4 or #5
#7 #3 and #6
MEDLINE Ovid 1946 to January 2019 1. exp Adrenal Cortex Hormones/
2. (glucocortico* or steroid* or dexamethasone or prednis* or hydrocorti-

sone or corticosteroid* or cortiso* or budesonide* or beclomethasone*).mp.
[mp=title, abstract, original title, name of substance word, subject heading
word, keyword heading word, protocol supplementary concept word, rare dis-
ease supplementary concept word, unique identifier]
3. 1 or 2
4. exp Hepatitis, Alcoholic/
5. (alcohol* and (liver or hepati*)).mp. [mp=title, abstract, original title, name

of substance word, subject heading word, keyword heading word, protocol
supplementary concept word, rare disease supplementary concept word,
unique identifier]
6. 4 or 5
Informed decisions.
(Continued)
7. 3 and 6
8. (random* or blind* or placebo* or meta-analys*).mp. [mp=title, abstract,

original title, name of substance word, subject heading word, keyword head-
ing word, protocol supplementary concept word, rare disease supplementary
concept word, unique identifier]
9. 7 and 8
Embase Ovid 1974 to January 2019 1. exp corticosteroid/
2. (glucocortico* or steroid* or dexamethasone or prednis* or hydrocorti-

sone or corticosteroid* or cortiso* or budesonide* or beclomethasone*).mp.
[mp=title, abstract, heading word, drug trade name, original title, device man-
ufacturer, drug manufacturer, device trade name, keyword]
3. 1 or 2
4. exp alcohol liver disease/
5. (alcohol* and (liver or hepati*)).mp. [mp=title, abstract, heading word, drug

trade name, original title, device manufacturer, drug manufacturer, device
trade name, keyword]
6. 4 or 5
7. 3 and 6
8. (random* or blind* or placebo* or meta-analys*).mp. [mp=title, abstract,

heading word, drug trade name, original title, device manufacturer, drug man-
ufacturer, device trade name, keyword]
9. 7 and 8
Science Citation In- 1900 to January 2019 #5 217 #4 AND #3

dex Expanded (Web of
Science) #4 1,347,943 TS=(random* or blind* or placebo* or meta-analys*)
#3 1,060 #2 AND #1
#2 36,574 TS=(alcohol* and (liver or hepati*))
#1 425,242 TS=(glucocortico* or steroid* or dexamethasone or prednis* or hy-

drocortisone or corticosteroid* or cortiso* or budesonide* or beclometha-
sone*)
eLibrary 1999 to January 2019 (glucocortico* or steroid* or dexamethasone or prednis* or hydrocortisone or

corticosteroid* or budesonide*) AND (alcohol* and (liver or hepati*))
Appendix 2. Level of liver enzymes (at the end of treatment)
Study Glucocorticosteroids Placebo/no intervention
Mean SD n Mean SD n
Campra 1973 62.5 3.72 22 79.2 5.83 28
Maddrey 1978 34.5 4 23 41.7 4.1 27

Informed decisions.
(Continued)
Theodossi 1982 164.0 — 28 118 — 32
Carithers 1989 74.9 4.19 36 119.9 7.79 31
—: data not reported; n: number of participants; SD: standard deviation.
Appendix 3. Prothrombin index (seconds)
Mean SD n Mean SD n
Percentage of normal
Campra 1973 77.5 2.5 36 83.1 2 31
Ramond 1992 48 0.5 32 45 0.5 29
At the end of treatment
Maddrey 1978 14 0.5 23 15.5 0.9 27
Theodossi 1982 13 — 28 10 — 32
Carithers 1989 15.5 1.25 36 16.25 1 31
Appendix 4. Level of serum albumin (g/L)
Mean SD n Mean SD n
Campra 1973 33.3 1.48 22 30.08 0.66 28
Maddrey 1978 33 2 23 30 2 27
Depew 1980 32 0.17 15 25.8 0.13 13
Carithers 1989 27 0.35 36 29 0.4 31
Ramond 1992 33 0.17 32 30 0.37 29
n: number of participants; SD: standard deviation.

Informed decisions.
Appendix 5. Level of bilirubin (μmol/L) (at the end of treatment)
Mean SD n Mean SD n
Campra 1973 43.2 2.9 22 63.95 6.84 28
Maddrey 1978 64.98 4.97 24 66.69 3.69 31
Depew 1980 68.4 6.5 15 136.8 11.79 13
Carithers 1989 125 8.12 36 190 17.9 31
Ramond 1992 100 7.1 32 150 18.8 29
n: number of participants; SD: standard deviation
Appendix 6. Age (years)
Mean SD n Mean SD n
Porter 1971 44.6 4.4 11 49.5 8.9 9
Campra 1973 43.1 11.1 22 42.7 8.1 28
Blitzer 1977 47.2 — 17 48.4 — 16
Maddrey 1978 40 8.5 25 42.3 11.1 32
Shumaker 1978 45.5 — 15 44.5 — 13
Depew 1980 49.8 2.1 15 48.2 2.3 13
Mendenhall 1984 51.5 8.2 90 50.4 9.2 88
Bories 1987 41 — 24 49 — 21
Carithers 1989 43.1 2 36 44.4 1.7 31
Ramond 1992 48.1 1.3 33 48.2 1.6 32
De 2014 42.7 0.4 31 41.3 7.8 31
Thursz 2015 48.6 9.8 277 47.9 9.2 276
Thursz 2015 49.3 10.6 274 48.8 10.3 276

Informed decisions.
WHAT'S NEW
Date Event Description
19 February 2019 New search has been performed We have revised the whole review so that it reflects current
Cochrane methodology.
We have excluded evaluation of imprecision with Trial Sequen-

tial Analysis from the GRADE assessment. In the previously pub-
lished review, assessment of imprecision with Trial Sequential
Analysis was presented in the 'Summary of findings' table.
28 January 2019 New citation required but conclusions No new randomised clinical trials identified for the review up-
have not changed date.
Discrepancies occurred in GRADE assessment and in conclusions

in certainty of evidence for the outcomes: serious adverse events
(from low to very low); liver-related mortality up to three months
following randomisation (from low to very low); and any compli-
cation, up to three months following randomisation (from low to
very low).
28 January 2019 New search has been performed Search for new trials performed 18 January 2019
CONTRIBUTIONS OF AUTHORS
CP, DV, and GC: drafted the review.
DN, ET, and CG: revised the review.
CP and DV: are the guarantors of the review.
All authors approved the review.
DECLARATIONS OF INTEREST
CP: none.
DV: none.
GC: none.
ET: none.
DN: none.
CG: none.
SOURCES OF SUPPORT
Internal sources
• The Cochrane Hepato-Biliary Group Editorial Team Office, Denmark.
External sources
• No sources of support supplied
DIFFERENCES BETWEEN PROTOCOL AND REVIEW

• Review author team changed.
• We removed the word 'alcohol' from the outcome "Alcohol liver-related mortality up to three months' follow-up after end of treatment"
as it was superfluous.
• Outcomes
* All-cause mortality is now better defined. Duration of treatment varied across the trials and also mortality data for up to three-
months' follow-up. This is why we have modified all-cause mortality to all-cause mortality at the end of treatment, up to three

Informed decisions.
months' follow-up after randomisation, and one year following randomisation. Thus, our primary time point has become "all-cause
mortality up to three months' follow-up after randomisation."
* Trials also reported data on liver-related mortality, any complication, and non-serious adverse events up to three months' follow-
up after randomisation. Thus, three months' follow-up after randomisation has also become our primary time point for the latter
outcomes. However, serious adverse events were reported mostly during the treatment period.
* Regarding exploratory outcomes, we created tables, as we did not have sufficient data for analysis.
• Originally we wrote in the protocol that "We will consider trials published before or after 1989 carefully, as the Maddrey's score was
modified in 1989 in order to stratify severe alcoholic hepatitis and define the group of people to be treated." However, it made also
sense to use the definitions of the trialists for mild and severe alcoholic hepatitis and we wrote: "For studies not reporting the Maddrey's
score, we used the classifications for mild and severe alcoholic hepatitis as provided by the trialists."
• As we did not have trials at low risk of bias, we calculated the diversity-adjusted required information size (DARIS) for our Trial Sequential
Analysis using data from all included trials.
• We calculated and reported the Trial Sequential Analysis-adjusted CI as a supplement to the naive 95% CI.
• We changed the risk of type I error from 2.5% (as originally planned based due to the three primary outcomes) into type I error of 1%,
as we performed Trial Sequential Analysis on all primary and secondary outcomes, including post-hoc time points.
Differences between previously published review version and this version

• 'Quality of evidence' was modified into 'certainty of evidence.'
• As per current Cochrane recommendations, we were advised to keep in separate assessments of imprecision with Trial Sequential
Analysis and GRADE in the 'Summary of findings' table. Therefore, we assessed imprecision with Trial Sequential Analysis and GRADE
as sensitivity analysis.
• Serious adverse events during treatment; liver-related mortality up to three months following randomisation; and number of
participants with any complications up to three months following randomisation in the GRADE 'Summary of findings' table.
• As per current Cochrane recommendations, we were advised not to include 'for-profit bias' risk domain in the overall bias risk
assessment tool. Therefore, we removed the domain. We planned to perform a subgroup analysis with trials without for-profit funding
compared to trials at risk of for-profit funding instead. However, only one trial seemed not be industry funded and the remaining trials
did not clearly report on industry funding.
• We performed a subgroup analysis on risk of bias (only one trial (Thursz 2015) fell into the group of trials at low risk of bias).
NOTES
Cochrane Reviews can be expected to have a high percentage of overlap in the methods section because of standardised methods. In
addition, overlap may be observed across two of our protocols as they share at least four common authors.
INDEX TERMS
Medical Subject Headings (MeSH)

Glucocorticoids [adverse effects] [*therapeutic use]; Hepatitis, Alcoholic [*drug therapy] [mortality]; Quality of Life; Randomized
Controlled Trials as Topic
MeSH check words

Adult; Aged; Female; Humans; Male; Middle Aged


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Cochrane

Glucocorticosteroids for people with alcoholic hepatitis (Review)

Pavlov CS, Varganova DL, Casazza G, Tsochatzis E, Nikolova D, Gluud C

Pavlov CS, Varganova DL, Casazza G, Tsochatzis E, Nikolova D, Gluud C.

Glucocorticosteroids for people with alcoholic hepatitis (Review)

Glucocorticosteroids for people with alcoholic hepatitis (Review) i

Glucocorticosteroids for people with alcoholic hepatitis (Review) ii

Glucocorticosteroids for people with alcoholic hepatitis

Editorial group: Cochrane Hepato-Biliary Group.

Data collection and analysis

PLAIN LANGUAGE SUMMARY

Glucocorticosteroids for people with alcoholic hepatitis

The date of the last search was 18 January 2019.

Glucocorticosteroids for people with alcoholic hepatitis (Review) 2

Reliability of the evidence

Glucocorticosteroids for people with alcoholic hepatitis (Review) 3

Settings: hospitals and clinics

Comparison: placebo or no intervention

The OIS was 7870 partici-

Cochrane Database of Systematic Reviews

GRADE Working Group: certainty of evidence grades

Cochrane Database of Systematic Reviews

BACKGROUND failure to respond to treatment and predicts a six-month mortality

Glucocorticosteroids for people with alcoholic hepatitis (Review) 7

Glucocorticosteroids for people with alcoholic hepatitis (Review) 9

Glucocorticosteroids for people with alcoholic hepatitis (Review) 10

• 30% to 60%: may represent moderate heterogeneity*; Trial Sequential Analysis

Glucocorticosteroids for people with alcoholic hepatitis (Review) 11

'Summary of findings' tables Results of the search

Glucocorticosteroids for people with alcoholic hepatitis (Review) 12

Figure 1. Study flow diagram.

Glucocorticosteroids for people with alcoholic hepatitis (Review) 13

Three trials followed participants up to one year (Mendenhall Outcomes

Glucocorticosteroids for people with alcoholic hepatitis (Review) 14

Glucocorticosteroids for people with alcoholic hepatitis (Review) 15

Glucocorticosteroids for people with alcoholic hepatitis (Review) 16

Glucocorticosteroids for people with alcoholic hepatitis (Review) 17

Effects of interventions all-cause mortality (random-effects RR 0.90, 95% CI 0.70 to 1.15;

Visual inspection of the funnel plot suggested publication bias or

Glucocorticosteroids for people with alcoholic hepatitis (Review) 18

Glucocorticosteroids for people with alcoholic hepatitis (Review) 19

Glucocorticosteroids for people with alcoholic hepatitis (Review) 20

Glucocorticosteroids for people with alcoholic hepatitis (Review) 21

Glucocorticosteroids for people with alcoholic hepatitis (Review) 22

Glucocorticosteroids for people with alcoholic hepatitis (Review) 23

Glucocorticosteroids for people with alcoholic hepatitis (Review) 24

Our Trial Sequential Analysis assessment of imprecision coincided

Glucocorticosteroids for people with alcoholic hepatitis (Review) 27

Glucocorticosteroids for people with alcoholic hepatitis (Review) 29

References to studies included in this review encephalopathy. Gastroenterology 1980;78(3):524-9. [MEDLINE:

Glucocorticosteroids for people with alcoholic hepatitis (Review) 30

Glucocorticosteroids for people with alcoholic hepatitis (Review) 31

Glucocorticosteroids for people with alcoholic hepatitis (Review) 32

Naveau 2004 {published data only}

Christensen 1995 Fisher 1922

Christensen 1999 Forrest 2005

Dominguez 2008 Gluud 2017

EASL 2018 Guyatt 2011b

Guyatt 2011e Higgins 2011a